Cephem compounds

ABSTRACT

Cephem compounds of the following formula are disclosed: ##STR1## wherein R 1  is amino or protected amino group. R 2  is H or an organic group, 
     R 3  is H or an organic group, 
     R 4  is H, lower alkyl, carboxy, protected carboxy, amino, protected amino or carbamoyl, Z=N or CH. The compounds are useful as antimicrobial agents.

The present invention relates to new cephem compounds andpharmaceutically acceptable salts thereof.

More particularly, it relates to new cephem compounds andpharmaceutically acceptable salts thereof, which have antimicrobialactivities, to processes for preparation thereof, to pharmaceuticalcomposition comprising the same, and to a method for treating infectiousdiseases in human being and animals.

Accordingly, one object of the present invention is to provide thecephem compounds and pharmaceutically acceptable salts thereof, whichare highly active against a number of pathogenic microorganisms.

Another object of the present invention is to provide processes for thepreparation of the cephem compounds and salts thereof.

A further object of the present invention is to provide pharmaceuticalcomposition comprising, as an active ingredient, said cephem compoundsor their pharmaceutically acceptable salts.

Still further object of the present invention is to provide a method fortreating infectious diseases caused by pathogenic microorganisms, whichcomprises administering said cephem compounds to infected human being oranimals.

The object cephem compounds of the present invention are novel and canbe represented by the following general formula (I) : ##STR2## whereinR¹ is amino or a protected amino group,

R² is hydrogen or an organic group,

R³ is hydrogen, lower alkyl, hydroxy(lower)alkyl, protectedhydroxy(lower)alkyl, amino(lower)alkyl, protected amino(lower)alkyl,carbamoyl(lower)alkyl, N,N-di(lower)alkylcarbamoyl(lower)alkyl or animino protective group,

R⁴ is hydrogen, lower alkyl, carboxy, protected carboxy, amino,protected amino or carbamoyl, and

Z is N or CH.

The cephem compound (I) of the present invention can be prepared byprocesses as illustrated in the following. ##STR3## wherein R¹, R², R³,R⁴ and Z are each as defined above,

R_(b) ³ is protected amino(lower)alkyl,

R_(c) ³ is amino(lower)alkyl and

R_(a) ² is hydroxy protective group.

The starting compound (II) is novel and can be prepared by processes asillustrated in the following. ##STR4## wherein R³ and R⁴ are each asdefined above,

R⁵ is a protected amino group,

R⁶ is a protected carboxy group,

Y is an acid residue, and

R_(a) ³ is an imino protective group.

Further, the compound (V) or a salt thereof can be prepared by themethods disclosed in the Preparations 1-4, 11-22, 31-52 and 58 describedlater or similar manners thereto.

Regarding the compounds (I), (Ia)-(Id) and (III), it is to be understoodthat said compounds include syn isomer, anti isomer and a mixturethereof. For example, with regard to the object compound (I), syn isomermeans one geometrical isomer having the partial structure represented bythe following formula : ##STR5## (wherein R¹, R² and Z are each asdefined above) and anti isomer means the other geometrical isomer havingthe partial structure represented by the following formula : ##STR6##(wherein R¹, R² and Z are each as defined above).

Regarding the other compounds, as mentioned above, the syn isomer andthe anti isomer can also be referred to the same geometrical isomers asillustrated for the compound (I).

Further, it is to be noted that the compound (I) can also exist in thetautomeric form, and such tautomeric equilibrium can be represented bythe following chems. ##STR7##

All of the above tautomeric isomers are included within the scope of thepresent invention, and in the present specification and claim, however,the object compound (I) is represented for the convenient sake by theformula (A).

Suitable pharmaceutically acceptable salts of the object compound (I)are conventional non-toxic salt and include a metal salt such as analkali metal salt (e.g. sodium salt, potassium salt, etc.) and analkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), anammonium salt, an organic base salt (e.g. trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt(e.g. acetate, trifluoroacetate, maleate, tartrate, methanesulfonate,benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acidsalt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate,etc.), or a salt with an amino acid (e.g. arginine, aspartic acid,glutamic acid, etc.), and the like.

In the above and subsequent descriptions of the present specification,suitable examples and illustrations of the various definitions which thepresent invention include within the scope thereof are explained indetail as follows.

The term "lower" is intended to mean a group having 1 to 6 carbonatom(s) preferably 1 to 4 carbon atom(s), unless otherwise provided.

Suitable "protected amino" and "protected amino moiety" in the term"protected amino(lower)alkyl" may include an acylamino or an amino groupsubstituted by a conventional protective group such as ar(lower)alkylwhich may have suitable substituent(s) (e.g. benzyl, trityl, etc.) orthe like.

Suitable "acyl moiety" in the term "acylamino" may include carbamoyl,substituted carbamoyl, aliphatic acyl group and acyl group containing anaromatic or heterocyclic ring. And, suitable examples of the said acylmay be N,N-di(lower)alkylcarbamoyl, lower alkanoyl (e.g. formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl,pivaloyl, etc.); lower alkoxycarbonyl (e.g. methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl,pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (e.g.mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl,butanesulfonyl, etc.); arenesulfonyl (e.g. benzenesulfonyl, tosyl,etc.); aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl,indancarbonyl, etc.); ar(lower)alkanoyl (e.g. phenylacetyl,phenylpropionyl, etc.); ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl,phenethyloxycarbonyl, etc.), and the like. The acyl moiety as statedabove may have suitable substituent(s) such as halogen (e.g. chlorine,bromine, iodine or fluorine) or the like.

Suitable "organic group" may include lower alkyl,

mono(or di or tri)halo(lower)alkyl (e.g. chloromethyl, dichloromethyl,trichloromethyl, bromomethyl, chloroethyl, dichloroethyl,trichloroethyl, fluoroethyl, trifluoroethyl, etc.),

lower alkenyl (e.g., vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or3 butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl,etc.),

lower alkynyl [e.g., ethynyl, 1-propynyl, propargyl, 1-methylpropargyl,1 or 2 or 3 butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or5-hexynyl, etc.),

aryl (e.g., phenyl, naphthyl, etc.),

ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl, phenethyl,phenylpropyl, etc.),

carboxy(lower)alkyl, protected carboxy(lower)alkyl, hydroxy(lower)alkyl,protected hydroxy(lower)alkyl, hydroxy protective group, and the like.

Suitable "protected carboxy" and "protected carboxy moiety" in the term"protected carboxy(lower)alkyl" may include esterified carboxy and thelike. And suitable examples of said ester may be the ones such as loweralkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropylester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester,t-pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.); loweralkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynylester (e.g. ethynyl ester, propynyl ester, etc.); lower alkoxyalkylester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethylester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.); loweralkylthioalkyl ester (e.g., methylthiomethyl ester, ethylthiomethylester, ethylthioethyl ester, isopropylthiomethyl ester, etc.); mono(ordi or tri)-halo(lower)alkyl ester (e.g. 2-iodoethyl ester,2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy(lower)alkyl ester(e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethylester, valeryloxymethyl ester, pivaloyloxymethyl ester,hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethylester, etc.); lower alkanesulfonyl(lower)alkyl ester (e.g., mesylmethylester, 2-mesylethyl ester etc.); ar(lower)alkyl ester, for example,phenyl(lower)alkyl ester which may have one or more suitablesubstituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzylester, phenethyl ester, trityl ester, benzhydryl ester,bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); aryl ester which may haveone or more suitable substituent(s) such as substituted or unsubstitutedphenyl ester (e.g. phenyl ester, tolyl ester, t-butylphenyl ester, xylylester, mesityl ester, cumenyl ester, 4-chlorophenyl ester,4-methoxyphenyl ester, etc.); tri(lower)alkyl silyl ester; loweralkylthioester (e.g. methylthioester, ethylthioester, etc.) and thelike.

Suitable "lower alkyl" and "lower alkyl moiety" in the terms"carboxy(lower)alkyl", "protected carboxy(lower)alkyl","hydroxy(lower)alkyl", "protected hydroxy(lower)alkyl","amino(lower)alkyl", "protected amino(lower)alkyl","carbamoyl(lower)alkyl", "N,N-di(lower)alkylcarbamoyl(lower)alkyl" and"N,N-di(lower)alkylcarbamoyl" may include straight or branched one suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,pentyl, hexyl or the like.

Suitable "imino protective group" may include an acyl group asexemplified above, and the like.

Suitable "hydroxy protective group" may include an acyl group asexemplified above, and the like.

Suitable "protected hydroxy moiety" in the term "protectedhydroxy(lower)alkyl" may be acyloxy group or the like.

Suitable "acyl moiety" in the term "acyloxy" may include an acyl groupas exemplified above, and the like.

Suitable "acid residue" may include halogen [e.g. chlorine, bromine,iodine, etc.], acyloxy such as sulfonyloxy [e.g. benzenesulfonyloxy,tosyloxy, mesyloxy, etc.], lower alkanoyloxy [e.g.acetyloxy,propionyloxy, etc.]or the like.

The processes for preparing the object compound of the present inventionare explained in detail in the following.

PROCESS 1

The compound (I) or a salt thereof can be prepared by reacting thecompound (II) or its reactive derivative at the amino group or a saltthereof with the compound (III) or its reactive derivative at thecarboxy group or a salt thereof.

Suitable reactive derivative at the amino group of the compound (II) mayinclude Schiff's base type imino or its tautomeric enamine type isomerformed by the reaction of the compound (II) with a carbonyl compoundsuch as aldehyde, ketone or the like; a silyl derivative formed by thereaction of the compound (II) with a silyl compound such asbis(trimethylsilyl)-acetamide, mono(trimethylsilyl)acetamide [e.g.N-(trimethylsilyl)acetamide], bis(trimethylsilyl)urea or the like; aderivative formed by reaction of the compound (II) with phosphorustrichloride or phosgene, and the like.

Suitable salts of the compound (II) and its reactive derivative can bereferred to the ones as exemplified for the compound (I).

Suitable reactive derivative at the carboxy group of the compound (III)may include an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like. Suitable examples of the reactivederivatives may be an acid chloride; an acid azide; a mixed acidanhydride with an acid such as substituted phosphoric acid [e.g.dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.],dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuricacid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphaticcarboxylic acid [e.g. acetic acid, propionic acid, butyric acid,isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.]or aromatic carboxylicacid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; anactivated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g.cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH₃)₂ N⁺=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesylphenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester,etc.], or an ester with a N-hydroxy compound [e.g.N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole,etc.], and the like. These reactive derivatives can optionally beselected from them according to the kind of the compound (III) to beused.

Suitable salts of the compound (III) and its reactive derivative can bereferred to the ones as exemplified for the compound (I).

The reaction is usually carried out in a conventional solvent such aswater, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvent may also be used in a mixture with water.

In this reaction, when the compound (III) is used in a free acid form orits salt form, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N'-carbonylbis-(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite, ethyl polyphosphate;isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);phosphorus trichloride; thionyl chloride, oxalyl chloride; lower alkylhaloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc.];triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, trichloromethyl chloroformate, phosphorusoxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic ororganic base such as an alkali metal bicarbonate, tri(lower)alkylamine,pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, orthe like.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to warming.

PROCESS 2

The compound (Ib) or a salt thereof can be prepared by subjecting thecompound [Ia) or a salt thereof to elimination reaction of the aminoprotective group.

Suitable method of this elimination reaction may include conventionalone such as hydrolysis, reduction and the like.

(i) For Hydrolysis :

The hydrolysis is preferably carried out in the presence of a base or anacid including Lewis acid.

Suitable base may include an inorganic base and an organic base such asan alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal[e.g. magnesium, calcium, etc.], the hydroxide or carbonate orbicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine,etc.], picoline, 1,5-diazabicyclo[4.3.0]-non-5-ene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, orthe like.

Suitable acid may include an organic acid [e.g. formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid,etc.]and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid,sulfuric acid, hydrogen chloride, hydrogen bromide, etc.]. Theelimination using Lewis acid such as trihaloacetic acid [e.g.trichloroacetic acid, trifluoroacetic acid, etc.]or the like ispreferably carried out in the presence of cation trapping agents [e.g.anisole, phenol, etc.].

The reaction is usually carried out in a solvent such as water, analcohol [e.g. methanol, ethanol, etc.], methylene chloride,tetrahydrofuran, a mixture thereof or any other solvent which does notadversely influence the reaction. A liquid base or acid can be also usedas the solvent. The reaction temperature is not critical and thereaction is usually carried out under cooling to warming.

(ii) For reduction

Reduction is carried out in a conventional manner, including chemicalreduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound(e.g. chromium chloride, chromium acetate, etc.}and an organic orinorganic acid (e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.).

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalysts (e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.), palladium catalysts (e.g. spongy palladium, palladium black,palladium oxide, palladium on carbon, colloidal palladium, palladium onbarium sulfate, palladium on barium carbonate, etc.), nickel catalysts(e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobaltcatalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts[e.g. reduced iron, Raney iron, etc.), copper catalysts (e.g. reducedcopper, Raney copper, Ullman copper, etc.) and the like. The reductionis usually carried out in a conventional solvent which does notadversely influence the reaction such as water, methanol, ethanol,propanol, N,N-dimethylformamide, or a mixture thereof. Additionally, incase that the above-mentioned acids to be used in chemical reduction arein liquid, they can also be used as a solvent. Further, a suitablesolvent to be used in catalytic reduction may be the above-mentionedsolvent, and other conventional solvent such as diethyl ether, dioxane,tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature of this reduction is not critical and thereaction is usually carried out under cooling to warming.

PROCESS 3

The compound (Id) or a salt thereof can be prepared by subjecting thecompound (lc) or a salt thereof to elimination reaction of the hydroxyprotective group. This reaction can be carried out in a similar mannerto that of the aforementioned Process 2, and therefore the reagent to beused and the reaction conditions (e.g., solvent, reaction temperature,etc.) can be referred to those of the Process 2.

The processes for preparing the starting compounds are explained in thefollowing.

PROCESS A - 1

The compound (VI) or a salt thereof can be prepared by reacting thecompound (IV) or a salt thereof with the compound (V) or a salt thereof.

The present reaction may be carried out in a solvent such as water,phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene,methylene chloride, ethylene chloride, formamide, N,N-dimethylformamide,methanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide,or any other organic solvent which does not adversely affect thereaction. The reaction temperature is not critical, and the reaction isusually carried out at ambient temperature, under warming or underheating.

PROCESS A 2

The compound (II) or a salt thereof can be prepared by subjecting thecompound (VI) or a salt thereof to elimination reaction of the aminoprotective group in R⁵ and the carboxy protective group in R⁶.

This reaction can be carried out in a similar manner to that of theaforementioned Process 2, and therefore the reagent to be used and thereaction conditions (e.g., solvent, reaction temperature, etc.) can bereferred to those of the Process 2.

PROCESS B

The compound (VIb) or a salt thereof can be prepared by subjecting thecompound (VIa) or a salt thereof to elimination reaction of the iminoprotective group. This reaction can be carried out in a similar mannerto that of the aforementioned Process 2, and therefore the reagent to beused and the reaction conditions (e.g., solvent, reaction temperature,etc.) can be referred to those of the Process 2.

PROCESS C

The compound (IIb) or a salt thereof can be prepared by subjecting thecompound (IIa) or a salt thereof to elimination reaction of the iminoprotective group. This reaction can be carried out in a similar mannerto that of the aforementioned Process 2, and therefore the reagent to beused and the reaction conditions (e.g., solvent, reaction temperature,etc.) can be referred to those of the Process 2.

The object compound (I) and pharmaceutically acceptable salts thereofare novel and exhibit high antimicrobial activity, inhibiting the growthof a wide variety of pathogenic microorganisms including Gram-positiveand Gram-negative microorganisms and are useful as antimicrobial agents.

Now in order to show the utility of the object compound (I), the testdata on MIC (minimal inhibitory concentration) of a representativecompound of the compound (I) are shown in the following.

Test method

In vitro antibacterial activity was determined by the two-foldagar-plate dilution method as described below.

One loopful of an overnight culture of each test strain inTrypticase-soy broth (10⁶ viable cells per ml) was streaked on heartinfusion agar (HI-agar) containing graded concentrations ofrepresentative test compound, and the minimal inhibitory concentration(MIC) was expressed in terms of μg/ml after incubation at 37° C. for 20hours.

Test compound (1)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

    ______________________________________                                        Test result                                                                   MIC (μg/ml)                                                                Test strain  Test Compound (1)                                                ______________________________________                                        E. coli 31   ≦0.025                                                    ______________________________________                                    

For therapeutic administration, the object compound (I) andpharmaceutically acceptable salts thereof of the present invention areused in the form of conventional pharmaceutical preparation whichcontains said compound as an active ingredient, in admixture withpharmaceutically acceptable carriers such as an organic or inorganicsolid or liquid excipient which is suitable for oral, parenteral andexternal administration. The pharmaceutical preparations may be in solidform such as tablet, granule, powder, capsule, or liquid form such assolution, suspension, syrup, emulsion, lemonade and the like.

If needed, there may be included in the above preparations auxiliarysubstances, stabilizing agents, wetting agents and other commonly usedadditives such as lactose, citric acid, tartaric acid, stearic acid,magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin,agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, andthe like.

While the dosage of the compound (I) may vary from and also depend uponthe age, conditions of the patient, a kind of diseases, a kind of thecompound (I) to be applied, etc., in general, amounts between 1 mg andabout 4,000 mg or even more per day may be administered to a patient. Anaverage single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, ofthe object compound (I) of the present invention may be used in treatingdiseases infected by pathogenic microorganisms.

The following Preparations and Examples are given for the purpose ofillustrating the present invention in more detail.

PREPARATION 1

A mixture of hydrazinoacetaldehyde diethyl acetal (21 g) andmethoxyacrylonitrile (11.8 g) in water (150 ml) was refluxed for 2 days.After the reaction mixture was cooled, to the mixture was added amixture of water and ethyl acetate. The separated organic layer waswashed with brine and dried over magnesium sulfate. The solvent wasevaporated and the residue was subjected to column chromatography onsilica gel using ethyl acetate as an eluent. Fractions containing theobject compound were combined and evaporated to give1-(2,2-diethoxyethyl)-5-aminopyrazole (5.45 g).

IR (Nujol) : 3300-3400, 2970, 1620, 1550, 1500 cm⁻¹

NMR (DMSO-d₆, δ) : 1.06 (6H, t, J=7 Hz), 3.31-3.48 (2H, m), 3.54-3.69(2H, m), 3.80 (2H, d, J=7 Hz), 4.75 (1H, t, J=7 Hz), 5.02 (2H, br s),5.26 (1H, d, J=2 Hz), 7.08 (1H, d, J=2 Hz)

PREPARATION 2

To a solution of 1-{2,2-diethoxyethyl)-5-aminopyrazole (5.4 g) inethanol (420 ml) was added aqueous 20% sulfuric acid solution (108 ml).The mixture was refluxed for 3 hours. After the reaction mixture wascooled, the mixture was adjusted to pH 8 with sodium carbonate (62 g).The insoluble material was filtered off and the filtrate was evaporatedto give 1H-imidazo[1,2-b]pyrazole (2.14 g).

NMR (DMSO-d₆, δ) : 5.62 (1H, d, J=2 Hz), 7.14 (1H, br s), 7.45 (1H, d,J=2 Hz), 7.49 (1H, br s), 10.97 (1H, br s)

PREPARATION 3

A mixture of acetic anhydride (3.68 ml) and formic acid (3 ml) wasstirred at room temperature for 1 hour. The solution was cooled in anice-bath and 1H-imidazo-[1,2-b]pyrazole (2.1 g) was added thereto. Themixture was stirred at room temperature for 1 hour. The reaction mixturewas evaporated and the residue was subjected to column chromatography onsilica gel using a mixture of n-hexane and ethyl acetate (1:1) as aneluent. Fractions containing the object compound were combined and thesolvent was evaporated to give 1-formyl-1H-imidazo[1,2-b]pyrazole (1.83g).

NMR (DMSO-d₆, δ) : 6.20 and 6.28 (total 1H, each d, J=2 Hz), 7.65-7.72(1H, m), 7.71 (1H, d, J=2 Hz), 7.87-7.92 (1H, m), 9.02 (1H, br s)

PREPARATION 4

The following compound was obtained according to a similar manner tothat of Preparation 3.

1-Formyl-6-methyl-1H-imidazo[1,2-b]pyrazole

NMR (DMSO-d₆, δ) : 2.32 (3H, s), 6.07 (1H, s), 7.43-7.63 (1H, m),7.63-7.80 (1H, m), 8.98 (1H, br s)

PREPARATION 5

To a solution of benzhydryl7β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylate (4.57 g)in N,N-dimethylformamide (5 ml) was added sodium iodide (1.33 g). Afterthe mixture was stirred at room temperature for 30 minutes,1-formyl-1H-imidazo[1,2-b]pyrazole (1.8 g) was added thereto. Themixture was stirred at the same condition for 20 hours. The reactionmixture was poured into a mixture of ethyl acetate (200 ml) and water(100 ml). The separated organic layer was washed with water and thenbrine, and dried over magnesium sulfate. The solvent was evaporated onvacuo, and the residue was pulverized with diisopropyl ether andcollected by filtration to give benzhydryl7β-t-butoxycarbonylamino-3-[1-formyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide (4.7 g).

IR (Nujol) : 1780, 1610 cm⁻¹

NMR (DMSO-d₆, δ) : 1.40 (9H, s), 3.38 (2H, br s), 5.15 (1H, d, J=5 Hz),5.28 and 5.45 (2H, ABq, J=16 Hz), 5.60 (1H, dd, J=5 Hz, 8 Hz), 6.59 (1H,d, J=3 Hz), 6.96 (1H, s), 7.00- 7.60 (l1H, m), 7.71 (1H, br s), 8.06(1H, d, J=8 Hz), 8.50 (1H, br s).

PREPARATION 6

The following compound was obtained according to a similar manner tothat of Preparation 5.

Benzhydryl7β-t-butoxycarbonylamino-3-[1-formyl-6-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

IR (Nujol) : 1775, 1710, 1590 cm⁻¹

NMR (DMSO-d₆, δ) : 1.40 (9H, s), 2.28 (3H, s), 3.29-3.50 (2H, br s),5.15 (1H, d, J=5 Hz), 5.39 (2H, br s), 5.64 (1H, dd, J=5 Hz, 8 Hz), 6.98(1H, s), 7.10-7.60 (l1H, m), 7.61 (1H, d, J=2 Hz), 7.88 (1H, d, J=3 Hz),8.10 (1H, d, J=8 Hz), 8.50 (1H, br s)

PREPARATION 7

To a suspension of benzhydryl7β-t-butoxycarbonylamino-3-[1-formyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate iodide [4.5 g) in a mixture of anisole [5 ml) andmethylene chloride (15 ml) was added dropwise trifluoroacetic acid (9ml) under ice-cooling. The mixture was stirred at room temperature for 2hours. The reaction mixture was poured into a mixture of diisopropylether (150 ml) and ethyl acetate (150 ml). The resultant powder wascollected by filtration and washed with diisopropyl ether and dried overphosphorus pentoxide in vacuo to give78-amino-3-[1-formyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate) (3.12 g).

IR (Nujol) : 1780, 1660, 1590 cm⁻¹

NMR (DMSO- d₆, δ) : 3.40 and 3.56 (2H, ABq, J=18 Hz), 5.05-5.5 (4H, m),6.64 (1H, d, J=3 Hz), 7.78 (1H, br s), 8.07 (1H, br s), 8.27 (1H, d, J=3Hz), 8.50 (1H, br s).

PREPARATION 8

The following compound was obtained according to a similar manner tothat of Preparation 7.

7β-Amino-3-[1-formyl-6-methyl-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

NMR (DMSO-d₆, δ) : 2.50 (3H, s), 3.32 and 3.48 (2H, ABq, J=1.8 Hz),5.00-5.50 (4H, m), 6.50 (1H, d, J=3 Hz), 7.71 (1H, br s), 8.05 (1H, brs), 8.50 (1H, br s).

PREPARATION 9

To a suspension of7β-amino-3-[1-formyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate) (3.0 g) in methanol (15 ml) was added conc.hydrochloric acid (1.5 ml). The mixture was stirred at room temperaturefor 2 hours. The reaction mixture was added dropwise to ethyl acetate(150 ml). The resultant powder was collected by filtration and washedwith diisopropyl ether and dried over phosphorus pentoxide in vacuo togive7β-amino-3-[5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylatetrihydrochloride (1.77 g).

NMR (D₂ O-NaHCO₃, δ) : 3.09 and 3.40 (2H, ABq, J=18 Hz), 4.40-5.50 (4H,m), 6.42 (1H, d, J=3 Hz), 7.45 (1H, d, J=2 Hz), 7.86 (1H, d, J=2 Hz),7.99 (1H, d, J=3 Hz).

PREPARATION 10

The following compound was obtained according to a similar manner tothat of Preparation 9.

7β-Amino-3-[6-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylatetrihydrochloride IR (Nujol) : 1780, 1700, 1600 cm⁻¹

NMR (D₂ O, δ) : 2.63 (3H, s), 3.30 and 3.57 (2H, ABq, J=18 Hz),5.07-5.67 (4H, m), 6.37 (1H, br s), 7.48 (1H, d, J=2 Hz), 7.89 (1H, d,J=2 Hz).

EXAMPLE 1

To a solution of7β-amino-3-[5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylatetrihydrochloride (0.9 g), N-trimethylsilylacetamide (2.8 g) andtetrahydrofuran (20 ml) was added2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetyl chloridehydrochloride (syn isomer) [0.59 g) under ice-cooling. The mixture wasstirred at room temperature for 2 hours. The reaction mixture was pouredinto ethyl acetate (200 ml). The resultant precipitate was collected byfiltration and washed with diisopropyl ether and dried over phosphoruspentoxide in vacuo. The powder was added to water and adjusted to pH 2.5with 1N hydrochloric acid and the insoluble material was filtered off.The aqueous solution was subjected to column chromatography on DiaionHP-20 [Trademark : prepared by Mitsubishi Kasei Corporation]usingaqueous 5% isopropyl alcohol solution as an eluent. Fractions containingthe object compound were combined, evaporated in vacuo to removeisopropyl alcohol and lyophilized to give7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer) (0.13 g).

IR (Nujol) : 1760, 1670, 1600 cm⁻¹.

NMR (D₂ O-NaHCO₃, δ) : 3.77, 3.33 (2H, ABq, J=18 Hz), 4.03 (3H, s), 5.13(1H, d, J=5 Hz), 5.Z2 (2H, br s), 5.80 (1H, d, J=5 Hz), 6.32 (1H, d, J=2Hz), 7.36 (1H, br s), 7.77 (1H, br s), 7.88 (1H, d, J=2 Hz).

EXAMPLE 2

A solution of7β-amino-3-[5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylatetrihydrochloride (0.8 g) in a mixture of water (8 ml) andtetrahydrofuran (16 ml) was adjusted to pH 7 with a saturated aqueoussodium bicarbonate solution and1-[2-[2-aminothiazol-4-yl)-2-methoxyiminoacetyl]-1H-benzotriazol-3-oxide(1.1 g) was added thereto at room temperature. The mixture was stirredfor 5 hours at 30° C. under pH 7. To the reaction mixture was addedethyl acetate (15 ml) and the separated aqueous layer was washed withethyl acetate (15 ml×2). The aqueous solution was adjusted to pH 4 with1N hydrochloric acid and washed with ethyl acetate (15 ml×3). Theaqueous solution was adjusted to pH 2 with 1N hydrochloric acid, andsubjected to column chromatography on Diaion HP-20 (30 ml) using 10%isopropyl alcohol as an eluent. Fractions containing the object compoundwere combined, concentrated to remove isopropyl alcohol and lyophilizedto give7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer) (0.26 g).

IR (Nujol) : 1770, 1670, 1600 cm⁻¹

NMR (D₂ O-NaHCO₃, δ) : 2.93 and 3.23 (2H, ABq, J=18 Hz), 3.83 (3H, s),5.02 (1H, d, J=5 Hz), 5.11 (2H, br s), 5.65 (1H, d, J=5 Hz), 6.21 (1H,d, J=3 Hz), 6.74 (1H, s), 7.20 (1H, d, J=2 Hz), 7.70 (1H, d, J=2 Hz),7.80 (1H, d, J=3 Hz).

EXAMPLE 3

The following compounds were obtained according to similar manners tothose of Examples 1 and 2.

(1)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[6-methyl-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer) IR (Nujol) : 1760, 1660, 1600 cm⁻¹

NMR (D₂ O-NaHCO₃, δ) : 2.48 (3H, s), 3.00 and 3.29 (2H, ABq, J=18 Hz),4.05 (3H, s), 5.14 (1H, d, J=5 Hz), 5.21 (2H, br s), 5.82 (1H, d, J=5Hz), 6.15 (1H, br s), 7.28 (1H, d, J=2 Hz), 7.75 (1H, d, J=2 Hz)

(2)7β-[2-[2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[6-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer) IR (Nujol) : 1760, 1680, 1600 cm⁻¹

NMR (D₂ O-NaHCO₃, δ) : 2.50 (3H, s), 3.00 and 3.33 (2H, ABq, J=18 Hz),3.98 (3H, s), 5.16 (1H, d, J=5 Hz), 5.25 (2H, br s), 5.79 (1H, d, J=5Hz), 6.20 (1H, br s), 6.88 (1H, s), 7.35 (1H, d, J=2 Hz), 7.61 (1H, d,J=2 Hz).

EXAMPLE 4

To a solution of7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylate(syn isomer) in water (0.2 ml) were added 2M sulfuric acid (0.2 ml) andethanol (0.2 ml). The mixture was stirred at room temperature for 1hour. The insoluble material was filtered off and the filtrate wasconcentrated to remove ethanol and lyophilized to give7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylatesulfate (syn isomer) (0.15 g). IR (Nujol) : 1770, 1670, 1610 cm⁻¹

NMR (D₂ O-NaHCO₃, δ) : 3.11 and 3.40 (2H, ABq, J=18 Hz), 3.97 (3H, s),5.16 (1H, d, J=5 Hz), 5.28 (2H, br s), 5.78 (1H, d, J=5 Hz), 6.41 (1H,d, J=3 Hz), 6.93 (1H, s), 7.45 (1H, d, J=2 Hz), 7.87 (1H, d, J=2 Hz),7.98 (1H, d, J=3 Hz).

PREPARATION 11

To a suspension of ethyl ethoxymethylenecyanoacetate (21.7 g) in ethanol(65 ml) was added dropwise a solution of hydrazinoacetaldehyde diethylacetal (19 g) in water (19 ml) under ice-cooling. The mixture wasstirred at 80° C. for 1.5 hours and evaporated to remove ethanol. To theresidue was 4N sodium hydroxide (64 ml), and the mixture was refluxedfor 1 hour. The mixture was adjusted to pH 3.5 with concentratedhydrochloric acid at 10°-20° C., and the resulting precipitate wascollected by filtration to give1-(2,2-diethoxyethyl)-4-carboxy-5-aminopyrazole (8.60 g). IR (Nujol) :3460, 3360, 1645, 1620, 1545 cm⁻¹

NMR (DMSO-d₆, δ) : 1.05 (6H, t, J=7 Hz), 3.41 (2H, q, J=7 Hz), 3.63 (2H,q, J=7 Hz), 3.98 (2H, d, J=5.5 Hz), 4.80 (1H, t, J=5.5 Hz), 6.14 (2H, brs), 7.44 (1H, s).

PREPARATION 12

To a solution of 1-(2,2-diethoxyethyl)-4-carboxy-5-aminopyrazole (1 g)in tetrahydrofuran [20 ml) was added 4N hydrochloric acid (10 ml), andthe solution was refluxed for 1 hour. The mixture was adjusted to pH 8with 5N sodium hydroxide (10 ml) and extracted with a mixture oftetrahydrofuran and ethyl acetate. The organic layer was dried overmagnesium sulfate and evaporated in vacuo to give1H-imidazo[1,2-b]pyrazole (235 mg).

NMR [DMSO-d₆, δ) : 5.62 (1H, d, J=2 Hz), 7.14 (1H, br s), 7.45 (1H, d,J=2 Hz), 7.49 (1H, br s), 10.97 (1H, br s).

PREPARATION 13

To a suspension of 62% sodium hydride (0.36 g) in N,N-dimethylformamide(6 ml) was added 1H-imidazo[1,2-b]-pyrazole (1 g) under ice-cooling.Then, thereto was added dropwise methyl iodide (0.58 ml) at the sametemperature. After the mixture was stirred at room temperature for 4hours, ethyl acetate was added thereto. The precipitate was filteredoff, and the organic solvent was evaporated in vacuo. The residue waspurified by column chromatography on silica gel to give1-methyl-1H-imidazo-1,2-b]pyrazole (0.9 g). IR (Neat) : 1590, 1550 cm⁻¹

NMR (DMSO-d₆, δ) : 3.57 (3H, s), 5.65 (1H, m), 7.09 (1H, m), 7.46 (2H,m).

PREPARATION 14

To a suspension of 5-amino-4-carboxy-1-(2,2-diethoxyethyl)pyrazole (4 g)in xylene (15.6 ml) was added dropwise 3.4M solution of sodiumbis(2-methoxyethoxy)-aluminum hydride in toluene (15.6 ml) at roomtemperature in an atmosphere of nitrogen. Then the mixture was refluxedfor 6 hours, and poured into a mixture of dichloromethane and water. Theprecipitate was filtered off, and the organic layer was separated anddried over magnesium sulfate. The organic solvent was evaporated invacuo to give 5-amino-4-methyl-1-[(E)-2-ethoxyvinyl]-pyrazole (598 mg).IR (Nujol) : 3440, 3280, 3150, 1665, 1625, 1585, 1520 cm⁻¹

NMR (DMSO-d₆, δ) 1.23 (3H, t, J=7 Hz), 1.79 (3H, s), 3.79 (2H, q, J=7Hz), 5.05 (2H, br s), 6.63 (1H, d, J=l1Hz), 6.95 (1H, s), 7.00 (1H, d,J=l1Hz).

PREPARATION 15

To a solution of 5-amino-4-methyl-1-[(E)-2-ethoxyvinyl]pyrazole (10.6 g)in tetrahydrofuran (212 ml) was added 4N hydrochloric acid, and themixture was refluxed for 3 hours. The reaction mixture was adjusted topH 8 under ice-cooling, thereto was added ethyl acetate (100 ml). Theseparated organic layer was dried over magnesium sulfate and evaporatedin vacuo to give 7-methyl-1H-imidazo[1,2-b]pyrazole (6.92 g) ascrystals. IR (Nujol) : 3100, 1620, 1500 cm⁻¹

NMR (DMSO-d 6) : 2.08 (3H, s), 7.10 (1H, m), 7.25 (1H, s), 7.40 (1H, m),10.89 (1H, br s).

PREPARATION 16

The following compound was obtained according to a similar manner tothat of preparation 3.

1-Formyl-7-methyl-1H-imidazo[1,2-b]pyrazole

IR (Nujol) : 3100, 1705, 1610, 1560 cm⁻¹

NMR (DMSO-d₆, δ) : 2.33 (3H, s), 7.49 (1H, s), 7.65 (1H, m), 7.80 (1H,m), 8.89 (1H, s).

PREPARATION 17

A mixture of 2-bromopropionaldehyde diethyl acetal (71 g) and hydrazinanhydride (43 ml) was dissolved in ethanol (284 ml). The solution wasrefluxed for 24 hours. The reaction mixture was evaporated to removeethanol. The residue was dissolved in aqueous 2N-sodium hydroxide (170ml) and extracted with diethyl ether (500 ml×3). The organic layer wasdried over magnesium sulfate and the solvent was distilled off in vacuoto give 2-hydrazinopropionaldehyde diethyl acetal (54.4 g).

NMR (DMSO-d₆, δ) : 0.93 (3H, d, J=6 Hz), 1.06-1.17 (6H, m), 2.65 (1H, q,J=6 Hz), 3.37-3.71 (4H, m), 4.26 (1H, d, J=6 Hz).

PREPARATION 18

To a solution of 2-(ethoxymethylene)-2-cyanoacetic acid ethyl ester(56.3 g) in ethanol (200 ml) was added dropwise2-hydrazinopropionaldehyde diethyl acetal (54 g) in ethanol (80 ml) atroom temperature. The mixture was refluxed for 4 hours. The reactionmixture was cooled at room temperature and the solvent was distilled offin vacuo to give the crude.1-(1-methyl-2,2-diethoxyethyl)-4-ethoxycarbonyl-5-aminopyrazole (100 g).The crude product (100 g) was dissolved in aqueous 4N-sodium hydroxide(170 ml) and the mixture was refluxed for 1 hour. The reaction mixturewas cooled at room temperature and washed with ethyl acetate (100 ml x2). The aqueous solution was adjusted to pH 3.5 with 6N-hydrochloricacid and stirred for 1 hour. The precipitate was collected byfiltration, washed with water and dried over phosphorus pentoxide togive 1-(1-methyl-2,2-diethoxyethyl)-4-carboxy-5-aminopyrazole (9.93 g).

IR (Nujol) : 3450, 3350, 1680, 1620, 1540 cm⁻¹

NMR (DMSO-d₆, δ) : 0.90 (3H, t, J=7 Hz), 1.15 (3H, t, J=7 Hz), 1.30 (3H,d, J=7 Hz), 3.12-3.70 (4H, m), 4.25-4.39 (1H, m), 4.62 (1H, d, J=7 Hz),6.17 (2H, br s), 7.45 (1H, s).

PREPARATION 19

1-(1-Methyl-2,2-diethoxyethyl)-4-carboxy-5-aminopyrazole (9.9 g) wasdissolved in tetrahydrofuran (200 ml) and thereto was added3N-hydrochloric acid (52 ml). The mixture was refluxed for 3 hours. Thereaction mixture was cooled at room temperature, adjusted to pH 6 withaqueous 30% potassium carbonate and extracted with ethyl acetate (100ml). Further the separated aqueous layer was extracted with ethylacetate {50 ml). The organic layer was combined and dried over magnesiumsulfate. The solvent was distilled off in vacuo. The residue waspulverized with isopropyl ether and the powder was collected byfiltration to give 3-methyl-1H-imidazo[1,2-b]pyrazole (3.01 g).

IR (Nujol) : 3450, 1600 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.29 (3H, s), 5.60 (1H, d, J=2 Hz), 6.86 (1H, s),7.45 (1H, d, J=2 Hz).

PREPARATION 20

A mixture of acetic anhydride (4.83 ml) and formic acid (3.86 ml) wasstirred at room temperature for 1 hour. The solution was cooled atice-bath and 3-methyl-1H-imidazo[1,2-b]pyrazole (3.1 g) was addedthereto. The mixture was stirred at the same condition for 1 hour. Thereaction mixture was evaporated and the residue was subjected to columnchromatography on silica gel using ethyl acetate as an eluent. Fractionscontaining the object compound were combined and the solvent wasevaporated to give 1-formyl-3-methyl-1H-imidazo[1,2-b]pyrazole (2.99 g).

IR (Nujol) : 1700, 1560 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.37 (3H, s), 6.27 (1H, br s), 7.46 (1H, br s), 7.70(1H, br s), 8.95 (1H, s).

PREPARATION 21

To a suspension of 62% sodium hydride (7.23 g) in N,N-dimethylformamide(70 ml) was added 1H-imidazo[1,2-b]-pyrazole [20 g) by portions underice-cooling. A solution of ehtyl bromoacetate (20.7 ml) inN,N-dimethylformamide (50 ml) was added thereto at the same condition.The mixture was stirred for 2 hours at room temperature. The reactionmixture was poured into a mixture of ethyl acetate (1 l) and water (500ml). The separated organic layer was washed with water and brine, anddried over magnesium sulfate. The solvent was evaporated and the residuewas subjected to column chromatography on silica gel using ethyl acetateas an eluent. Fractions containing the object compound were combined andevaporated in vacuo to give1-ethoxycarbonylmethyl-1H-imidazo[1,2-b]pyrazole (25 g).

NMR (DMSO-d₆, δ) : 1.21 (3H, t, J=7 Hz), 4.15 (2H, q, J=7 Hz), 4.89 (2H,s), 5.69 (1H, d, J=2 Hz), 7.15 (1H, d, J=3 Hz), 7.46 (1H, d, J=3 Hz),7.54 (1H, d, J=2 Hz).

PREPARATION 22

To a suspension of lithium aluminum hydride (1.57 g) in tetrahydrofuran(80 ml) was dropwise added a solution of1-ethoxycarbonylmethyl-1H-imidazo[1,2-b]pyrazole (8 g) intetrahydrofuran (40 ml) at 50° C. The mixture was refluxed for 1 hour.The reaction mixture was cooled under ice-bath. To a cooled mixture wasadded sodium fluoride (6.95 g) and then water (2.23 ml) was addedthereto under ice-cooling. The insoluble material was filtered off andthe filtrate was evaporated to give the crystals. The crystals werewashed with isopropyl ether and dried to give1-(2-hydroxyethyl)-1H-imidazo[1,2-b]-pyrazole (4.82 g).

IR (Nujol) : 1720, 1600 cm⁻¹.

NMR (DMSO-d₆, δ) : 3.70 (2H, q, J=5 Hz), 3.94 (2H, t, J=5 Hz), 4.93 (1H,t, J=5 Hz), 5.69 (1H, d, J=2 Hz), 7.14 (1H, d, J=3 Hz), 7.45 (1H, d, J=3Hz), 7.49 (1H, d, J=2 Hz).

PREPARATION 23

The following compounds were obtained according to a similar manner tothat of Preparation 5.

(1) Benzhydryl7β-t-butoxycarbonylamino-3-[1-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

IR (Nujol) : 1780, 1720, 1605 cm⁻¹.

NMR (DMSO-d₆, δ) : 1.42 (9H, s), 3.33 (2H, br s), 3.82 (3H, s), 5.12 and5.33 (2H, ABq, J=15 Hz), 5.15 (1H, d, J=5 Hz), 5.61 (1H, dd, J=8 Hz, 5Hz), 6.69 (1H, d, J=3 Hz), 6.96 (1H, s), 7.17-7.51 (10H, m), 7.71 (1H,m), 7.79 (1H, m), 7.95 (1H, d, J=8 Hz), 8.15 (1H, m).

(2) Benzhydryl7β-t-butoxycarbonylamino-3-[1-(2-hydroxyethyl)-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

NMR (DMSO-d₆, δ) : 1.40 (9H, s), 3.42 (2H, br s), 3.75 (2H, q, J=5 Hz),4.12 (2H, t, J=5 Hz}, 5.04 (1H, t, J=5 Hz), 5.17 (1H, d, J=5 Hz), 5.28and 5.45 (2H, ABq, J=16 Hz), 5.65 (1H, dd, J=5, 8 Hz), 6.69 (1H, d, J=3Hz), 6.96 (1H, s), 7.26-7.51 (10H, m), 7.76 (1H, br s), 7.84 (1H, br s),8.07 (1H, d, J=8 Hz), 8.13 (1H, d, J=3 Hz)

PREPARATION 24

To a suspension of benzhydryl7β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylate [25.4 g)and sodium iodide (7.4 g) in N,N-dimethylformamide (25 ml) was added1-formyl-1H-imidazo[1,2-b]pyrazole (10 g) at room temperature. Afterbeing stirred for 20 hours at the same temperature, the mixture waspoured into a mixture of ethyl acetate and ice-water. The separatedorganic layer was washed with water and brine, and dried over magnesiumsulfate. The organic solvent was evaporated in vacuo to give benzhydryl7β-t-butoxycarbonylamino-3-[5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide (31.1 g).

NMR (DMSO-d₆, δ) : 1.41 (9H, s), 3.43 (2H, br s), 5.17 (1H, d, J=5 Hz),5.38 (2H, m), 5.61 (1H, dd, J=8 Hz, 5 Hz), 6.58 (1H, d, J=3 Hz), 6.97(1H, s), 7.15-7.53 (10H, m), 7.70 (1H, m), 7.79 (1H, m), 7.97 (1H, d,J=8 Hz), 8.15 (1H, m).

PREPARATION 25

To a solution of benzhydryl7β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylate (6.2 g)in N,N-dimethylformamide (6 ml) was added sodium iodide (1.8 g). Afterthe mixture was stirred at room temperature for minutes. Thereto wasadded 1-formyl-3-methyl-1H-imidazo[1,2-b]pyrazole (2.9 g). The mixturewas stirred at the same condition for 30 hours. The reaction mixture waspoured into a mixture of ethyl acetate (180 ml) and water (120 ml). Theseparated organic layer was washed with water and then brine, and driedover magnesium sulfate. The solvent was evaporated in vacuo and theresidue was pulverized with isopropyl ether and collected by filtrationto give benzhydryl7β-t-butoxycarbonylamino-3-[3-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate iodide (4.66 g).

IR (Nujol) : 1780, 1610 cm⁻¹.

NMR (DMSO-d₆, δ) : 1.41 (9H, s), 2.31 (3H, s), 3.30 and 3.45 (2H, ABq,J=18 Hz), 5.16 (1H, d, J=5 Hz), 5.36 and 5.57 (2H, ABq, J=16 Hz),5.57-5.66 (1H, m), 6.53 (1H, d, J=3 Hz), 6.95 (1H, s), 7.00-7.50 (11H,m), 8.18 (1H, d, J=3 Hz).

PREPARATION 26

The following compound was obtained according to similar manners tothose of Preparation 24 and Preparation 25.

Benzhydryl7β-t-butoxycarbonylamino-3-[7-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate

IR (Nujol) : 3280, 1790, 1715, 1680 cm⁻¹.

NMR (DMSO-d₆, δ) : 1.41 (9H, s), 2.17 (3H, s), 3.40 (2H, br s), 5.11 and5.36 (2H, ABq, J=15 Hz), 5.13 (1H, d, J=5 Hz), 5.58 (1H, dd, J=8 Hz, 5Hz), 6.92 (1H, s), 7.08-7.46 (10H, m), 7.67 (1H, m), 7.77 (1H, m), 7.85(1H, m), 7.92 (1H, d, J=8 Hz).

PREPARATION 27

To a suspension of benzhydryl7β-t-butoxycarbonylamino-3-[3-methyl-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylateiodide [4.6 g) in a mixture of anisole (4.6 ml) and dichloromethane (14ml) was added dropwise trifluoroacetic acid (9.2 ml) under ice-cooling.The mixture was stirred at room temperature for 2 hours. The reactionmixture was poured into a mixture of isopropyl ether (140 ml) and ethylacetate (140 ml). The resultant powder was collected by filtration andwashed with isopropyl ether and dried over phosphorus pentoxide in vacuoto give 7β-amino-3-[3-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate bis(trifluoroacetate)(2.75 g).

IR (Nujol) : 1780, 1660, 1590 cm⁻¹.

PREPARATION 28

The following compound were obtained according to a similar manner tothat of Preparation 27.

(1)7β-Amino-3-[1-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

IR (Nujol) : 1780, 1660, 1600 cm⁻¹.

NMR (D₂ O, δ) : 3.28 and 3.55 (2H, ABq, J=18 Hz), 3.83 (3H, s), 5.18(1H, d, J=5 Hz), 5.29 (1H, d, J=5 Hz), 5.41 (2H, br s), 6.25 (1H, d, J=3Hz), 7.43 (1H, m), 7.87 (1H, m), 8.04 (1H, d, J=3 Hz).

(2)7β-Amino-3-[7-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

IR (Nujol) : 1780, 1670, 1610 cm⁻¹.

NMR (D₂ O, δ) : 2.20 (3H, s), 3.37 and 3.53 (2H, ABq, J=18 Hz), 5.24(2H, s), 5.41 (2H, s), 7.79 (1H, s), 8.06 (2H, m).

(3)7β-Amino-3-[1-(2-hydroxyethyl)-5-(1H-imidazo[1,2-b]-pyrazolio)methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

IR [Nujol) : 1780, 1670, 1590 cm⁻¹.

NMR (DMSO-d₆, δ) : 3.35 and 3.54 (2H, ABq, J=18 Hz), 3.76 (2H, q, J=5Hz), 4.22 (2H, t, J=5 Hz), 4.70 (1H, t, J=5 Hz), 5.21 (2H, br s), 5.47(2H, br s), 6.73 (1H, d, J=3 Hz), 7.82 (1H, br s), 8.12 (1H, br s), 8.27(1H, d, J=3 Hz).

PREPARATION 29

To a solution of benzhydryl7β-t-butoxycarbonylamino-3-[5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide (31 g) in formic acid (124 ml) was added conc. hydrochloric acid[7.67 ml) at room temperature. After being stirred for 2 hours at thesame temperature, the mixture was poured into a mixture of acetone (1 l)and ethyl acetate (2 l). The resulting precipitate was collected byfiltration to give7β-amino-3-[5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatedihydrochloride hydroiodide (17.39 g).

NMR (D₂ O, δ) : 3.30 and 3.59 (2H, ABq, J=18 Hz), 5.21 (1H, d, J=5 Hz),5.32 (1H, d, J=5 Hz), 5.48 (2H, br s), 6.48 (1H, d, J=3 Hz), 7.50 (1H,m), 7.88 (1H, m), 8.06 (1H, m).

PREPARATION 30

A solution of7β-amino-3-[5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylatedihydrochloride hydroiodide [15.3 g) in water (61.2 ml) was subjected tocolumn chromatography on Diaion HP 20 (107.1 ml) and eluted with water.The desired fractions (120 ml) was obtained and isopropyl alcohol (500ml) was added thereto under ice-cooling. The mixture was stirred for 2hours at the same temperature, and the resulting precipitate wascollected by filtration to give7β-amino-3-[(5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatehydrochloride (7.0 g) as crystals.

IR (Nujol) 3550, 3390, 1780, 1650, 1605 cm⁻¹.

NMR (D₂ O, δ) : 3.26 and 3.50 (2H, ABq, J=18 Hz), 5.16 (1H, d, J=5 Hz),5.26 (1H, d, J=5 Hz), 5.35 (2H, br s), 6.47 (1H, d, J=3 Hz), 7.51 (1H,m), 7.90 (1H, m), 8.05 (1H, m).

EXAMPLE 5

To a solution of a mixture of7β-amino-3-[1-(2-hydroxyethyl)-5-{1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatebls(trifluoroacetate) (1.2 g) and N-trimethylsilylacetamide (2.66 g) intetrahydrofuran (24 ml) was added2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl chloride hydrochloride (synisomer) (0.62 g) under ice-cooling. The mixture was stirred for 2 hoursat the same condition. The reaction mixture was poured into ethylacetate (240 ml). The resultant precipitate was collected by filtration,washed with isopropyl ether and dried over phosphorus pentoxide invacuo. The crude product was dissolved in water and adjusted to pH 2.5with 1N-hydrochloric acid. The aqueous solution was subjected to columnchromatography on Diaion HP-20 using aqueous 10% isopropyl alcohol as aneluent. Fractions containing the object compound were combined andevaporated in vacuo to remove isopropyl alcohol and lyophilized to give7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[1-(2-hydroxyethyl)-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate (syn isomer) (0.50 g).

IR (Nujol) : 1760, 1660, 1600 cm⁻¹.

NMR (D₂ O, δ) : 3.13 and 3.44 (2H, ABq, J=18 Hz), 3.97 (3H, s),3.85-4.10 (2H, m), 4.27 (2H, t, J=5 Hz), 5.17 (1H, d, J=5 Hz), 5.29 (2H,br s), 5.78 (1H, d, J=5 Hz), 6.48 (1H, d, J=3 Hz), 6.90 (1H, s), 7.47(1H, br s), 7.93 (1H, br s), 8.01 (1H, d, J=3 Hz).

EXAMPLE 6

The following compounds were obtained according to similar manners tothose of Examples 1, 2 and 5.

(1)7β-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-[5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate (syn isomer)

IR (Nujol) 1770, 1665, 1610, 1520 cm⁻¹.

NMR (DMSO-d₆, δ) : 1.20 (3H, t, J=7 Hz), 2.93 and 3.35 (2H, ABq, J=18Hz), 4.05 (2H, q, J=7 Hz), 5.05 (1H, d, J=5 Hz), 5.20-5.50 (2H, m), 5.66(1H, dd, J=5 Hz, 8 Hz), 6.45 (1H, d, J=5 Hz), 6.68 (1H, s), 7.15 (2H, brs), 7.49-7.62 (1H, m), 8.18 (1H, d, J=5 Hz), 8.38-8.55 (1H, m), 9.46(1H, d, J=8 Hz)

(2)7β-[2-(2-Aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1770, 1665, 1610, 1530 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.90 and 3.35 (2H, ABq, J=18 Hz), 4.36-4.70 (2H, m),5.05 (1H, d, J=5 Hz), 5.10-5.48 (2H, m), 5.63 (1H, dd, J=5 Hz, 8 Hz),5.60-6.15 (1H, m), 6.46 (1H, d, J=3 Hz), 6.68 (1H, s), 7.16 (2H, br s),7.48-7.63 (1H, m), 8.18 (1H, d, J=3 Hz), 8.35-8.55 (1H, m), 9.55 (1H, d,J=8 Hz).

(3)7β-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-[1-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1770, 1660, 1625, 1605, 1525 cm⁻¹.

NMR (D₂ O+NaHCO₃, δ) : 1.30 (3H, t, J=7 Hz), 3.15 and 3.43 (2H, ABq,J=18 Hz), 3.83 (3H, s), 4.26 (2H, q, J=7 Hz), 5.20 (1H, d, J=5 Hz), 5.28(2H, br s), 5.80 (1H, d, J=5 Hz), 6.46 (1H, d, J=3 Hz), 6.90 (1H, s),7.25-7.46 (1H, m), 7.86 (1H, d, J=3 Hz), 7.93-8.06 (1H, m).

(4)7β-[2-(2-Aminothiazol-4-yl)-2-allyloxyiminacetamido]-3-[1-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylate (syn isomer)

IR (Nujol) : 1765, 1660, 1620, 1595, 1525 cm⁻¹.

NMR (D₂ O, δ) : 3.13 and 3.45 (2H, ABq, J=18 Hz), 3.90 (3H, s),5.05-5.20 (2H, m), 5.23 (1H, d, J=5 Hz), 5.30-5.58 (2H, m), 5.80 (1H, d,J=5 Hz), 5.85-6.33 (1H, m), 6.43 (1H, d, J=3 Hz), 6.96 (1H, s),7.30-7.50 (1H, m), 7.80-7.91 (1H, m), 8.01 (1H, d, J=3 Hz).

(5)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[5-(1H-imidazo[1,2-b]pyrazolio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 3300, 1760, 1660, 1600 cm⁻¹.

NMR (D₂ O, δ) : 1.30 (3H, t, J=7 Hz), 3.11 and 3.39 (2H, ABq, J=18 Hz),4.33 (2H, q, J=7 Hz), 5.18 (1H, d, J=5 Hz), 5.28 (2H, br s), 5.83 (1H,d, J=5 Hz), 6.38 (1H, d, J=3 Hz), 7.43 (1H, m), 7.87 (1H, m), 7.98 (1H,d, J=3 Hz).

(6)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-[1-carboxy-1-methylethoxyiminoacetamido]-3-[5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) 3120, 1765, 1660, 1620 cm⁻¹.

NMR (D₂ O+NaHCO₃, δ) : 1.50 (6H, s), 3.19 and 3.39 (2H, ABq, J=18 Hz),5.18 (1H, d, J=5 Hz), 5.28 (2H, br s), 5.82 (1H, d, J=5 Hz), 6.39 (1H,d, J=3 Hz), 7.43 (1H, m), 7.88 (1H, m), 7.98 (1H, d, J=3 Hz).

(7)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[5-(1H-imidazo[1,2-b]pyrazolio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 3300, 3120, 1760, 1660, 1600 cm⁻¹.

NMR (D₂ O+DC1, δ) : 3.28 and 3.63 (2H, ABq, J=18 Hz), 4.92 (2H, m), 5.19and 5.63 (2H, ABq, J=15 Hz), 5.29 (1H, d, J=5 Hz), 5.31-6.21 (3H, m),5.91 (1H, d, J=5 Hz), 6.51 (1H, d, J=3 Hz), 7.53 (1H, m}, 7.89 (1H, m),8.07 (1H, m)

(8)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1-methyl-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1760, 1670, 1595 cm⁻¹.

NMR (D₂ O+DC1, δ) : 3.08 and 3.43 (2H, ABq, J=18 Hz), 3.64 (3H, s), 3.91(3H, s), 5.08 (1H, d, J=5 Hz), 5.11 and 5.38 (2H, ABq, J=15 Hz), 5.64(1H, d, J=5 Hz), 6.34 (1H, d, J=3 Hz), 7.25 (1H, m), 7.65 (1H, m), 7.86(1H, d, J=3 Hz).

(9)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]3-[1-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1765, 1660, 1605 cm⁻¹.

NMR (D₂ O, δ) : 3.11 and 3.45 (2H, ABq, J=18 Hz), 3.82 (3H, s), 3.98(3H, s), 5.19 (1H, d, J=5 Hz), 5.28 (2H, br s), 5.78 (1H, d, J=5 Hz),6.48 (1H, d, J=3 Hz), 6.90 (1H, s), 7.40 (1H, m), 8.02 (1H, d, J=3 Hz).

(10)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[1-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 3300, 1765, 1665, 1600 cm⁻¹.

NMR (D₂ O+NaHCO₃, δ) : 1.48 (6H, s), 3.08 and 3.39 (2H, ABq, J=18 Hz),3.79 (3H, s), 5.17 (1H, d, J=5 Hz), 5.25 (2H, br s), 5.80 (1H, d, J=5Hz), 6.45 (1H, d, J=3 Hz), 7.38 (1H, d, m), 7.87 (1H, m), 7.98 (1H, d,J=3 Hz).

(11)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[1-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylate[syn isomer)

IR (Nujol) : 3270, 1760, 1660, 1595 cm⁻¹.

NMR (D₂ O+DC1, δ) : 1.33 (3H, t, J=7 Hz), 3.29 and 3.65 (2H, ABq, J=18Hz), 3.86 (3H, s), 4.43 (2H, q, J=7 Hz), 5.32 (1H, d, J=5 Hz), 5.35 and5.62 (2H, ABq, J=15 Hz), 5.86 (1H, d, J=5 Hz), 6.55 (1H, d, J=3 Hz),7.46 (1H, d, J=2 Hz), 7.86 (1H, d, J=2 Hz), 8.08 (1H, d, J=3 Hz).

(12)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[1-methyl-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 3120, 1770, 1670, 1605 cm⁻¹.

NMR (D₂ O, δ) : 3.27 and 3.63 (2H, ABq, J=18 Hz), 3.87 (3H, s), 4.88(2H, br s), 5.18-5.67 (2H, m), 5.28 (1H, d, J=5 Hz), 5.33 and 5.59 (2H,ABq, J=15 Hz), 5.87 (1H, d, J=5 Hz), 5.91-6.25 (1H, m), 6.53 (1H, d, J=3Hz), 7.43 (1H, m), 7.84 (1H, m), 8.03 (1H, d, J=3 Hz).

(13)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[7-methyl-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 3300, 1760, 1665, 1605 cm⁻¹.

NMR (D₂ O, δ) : 2.24 (3H, s), 3.27 and 3.60 (2H, ABq, J=18 Hz), 4.10(3H, s), 5.24 and 5.52 (2H, ABq, J=15 Hz), 5.28 (1H, d, J=5 Hz), 5.88(1H, d, J=5 Hz), 7.47 (1H, m), 7.79 (2H, m).

(14)7β-[2-[2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[7-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR [Nujol) : 3300, 1770, 1670, 1610 cm⁻¹.

NMR (D₂ O, δ) : 1.26 (3H, s), 3.29 and 3.61 (2H, ABq, J=18 Hz), 4.08(3H, s), 5.28 (1H, d, J=5 Hz), 5.29 and 5.53 (2H, ABq, J=15 Hz), 5.82(1H, d, J=5 Hz), 7.12 (1H, s), 7.48 (1H, m), 7.80 (2H, m).

(15)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[3-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1770, 1670, 1610 cm⁻¹.

NMR (D₂ O, δ) : 2.54 (3H, s), 3.27 (2H, br s), 4.05 (3H, s), 5.17 (1H,d, J=5 Hz), 5.18 and 5.57 (2H, ABq, J=15 Hz), 5.84 (1H, d, J=5 Hz), 6.33(1H, d, J=3 Hz), 7.10 (1H, br s), 7.88 (1H, d, J=3 Hz).

(16)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[3-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1760, 1660, 1600 cm⁻¹.

NMR (D₂ O, δ) : 2.57 (3H, s), 3.27 (2H, br s), 3.98 (3H, s), 5.17 (1H,d, J=5 Hz), 5.18 and 5.57 (2H, ABq, J=15 Hz), 5.80 (1H, d, J=5 Hz), 6.33(1H, d, J=3 Hz), 6.92 (1H, s), 7.09 (1H, br s), 7.88 (1H, d, J=3 Hz).

(17)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1-(2-hydroxyethyl)-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1760, 1660, 1590 cm⁻¹.

NMR (D₂ O, δ) : 3.15 and 3.44 (2H, ABq, J=18 Hz), 3.95 (2H, t, J=5 Hz),4.29 (2H, t, J=5 Hz), 5.17 (1H, d, J=5 Hz), 5.30 (1H, br s), 5.82 (1H,d, J=5 Hz), 6.49 (1H, d, J=3 Hz), 7.48 (1H, d, J=2 Hz), 7.92 (1H, d, J=2Hz), 8.02 (1H, d, J=3Hz).

(18)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[1-(2-hydroxyethyl)-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1760, 1660, 1500 cm⁻¹.

NMR (D₂ O, δ) : 1.39 (3H, t, J=8Hz), 3/22 and 3.52 (2H, ABq, J=18Hz),4.03 (2H, t, J=5Hz), 4.37 (2H, t, J=5Hz), 4.42 (2H, q, J=8Hz), 5.37 (1H,d, J=5Hz), 5.38 (1H, br s), 5.91 (1H, d, J=5Hz), 6.57 (1H, d, J=3Hz),7.57 (1H, d, J=2Hz), 8.01 (1H, d, J=2Hz), 8.11 (1H, d, J=3Hz).

PREPARATION 31

The following compounds were obtained according to a similar manner tothat of Preparation 13.

(1) 1,7-Dimethyl-1H-imidazo[1,2-b]pyrozole

IR (Nujol) : 3100, 1660, 1610, 1535 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.19 (3H, s), 3.68 (3H, s), 7.04 (1H, br s), 7.25(1H, s), 7.40 (1H, br s).

(2) 1-Methyl-7-cyano-1H-imidazo-[1,2-b]pyrozole

IR (Nujol) : 3100-3200, 2210, 1620 cm⁻¹.

NMR (DMSO-d₆, δ) : 3.78 (3H, s), 7.40 (1H, d, J=2Hz), 7.82 (1H, d,J=2Hz), 8.09 (1H, d, J=1Hz).

(3) 1-Methyl-7-methoxycarbonyl-1H-imidazo[1,2-b]pyrazole

IR (Nujol) : 3150, 1690, 1600 cm⁻¹.

NMR (DMSO-d₆, δ) : 3.74 (3H, s), 3.95 (3H, s), 7.31 (1H, d, J=2Hz), 7.74(1H, d, J=2Hz), 7.93 (1H, s).

(4) 1,2-Dimethyl-1H-imidazo[1,2-b]pyrazole

IR (Neat) : 1600 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.23 (3H, s), 3.49 (3H, s), 5.63 (1H, d, J=2 Hz),7.29 (1H, s), 7.38 (1H, d, J=2 Hz)

PREPARATION 32

To a solution of 1-ethoxycarbonylmethyl-1H-imidazo-[1,2-b]pyrazole (35g) in ethanol (180 ml) was added 28% ammonium hydroxide solution {110ml). The mixture was stirred at room temperature for two hours. Theresultant precipitate was collected by filtration, washed with isopropylether and dried to give 1-carbamoylmethyl-1H-imidazo[1,2-b]pyrazole[18.0 g).

NMR (DMSO-d₆, δ) : 4.55 (2H, s), 5.63 (1H, d, J=2 Hz), 7.11 (1H, d, J=3Hz), 7.28 (1H, br s), 7.45 (1H, d, J=3 Hz), 7.51 (1H, d, J=2 Hz), 7.58(1H, br s).

PREPARATION 33

The following compound was obtained by treating1-(1-methoxycarbonyl-1-methylethyl)-1H-imidazo[1,2-b]-pyrazole accordingto a similar manner to that of Preparation 32.

1-(1-Carbamoyl-1-methylethyl)-1H-imidazo[1,2-b]-pyrazole

NMR (DMSO-d₆, δ) : 1.68 (6H, s), 5.61 (1H, d, J=2 Hz), 7.20 (1H, d, J=3Hz), 7.45 (1H, d, J=3 Hz), 7.27 (2H, br s), 7.55 (1H, d, J=2 Hz).

PREPARATION 34

To a suspension of lithium aluminum hydride (7.86 g) in tetrahydrofuran(500 ml) was added 1-carbamoylmethyl-1H-imidazo[1,2-b]pyrazole (17 g) at50° C.

The mixture was refluxed for 3 hours. The reaction mixture was cooled at5° C. Sodium fluoride (34.8 g) and water (11.2 ml) were added theretounder ice-cooling. The insoluble material was filtered off and thefiltrate was evaporated to give1-(2-aminoethyl)-1H-imidazo[1,2-b]-pyrazole.

PREPARATION 35

A mixture of acetic anhydride {19.5 ml) and formic acid [15.7 ml) wasstirred at room temperature for 45 minutes. The mixture was cooled at 5°C and -(2-aminoethyl)-1H-imidazo[1,2-b]pyrazole was added thereto. Themixture was stirred for 1 hour under ice-cooling. The reaction mixturewas evaporated and the residue was subjected to column chromatography onsilica gel using a mixture of ethyl acetate and methanol (9:1) aseluent. Fractions containing the object compound were combined andevaporated to give 1-(2-formylaminoethyl)-1H-imidazo[1,2-b]pyrazole (7g).

NMR (DMSO-d₆, δ) : 3.36-3.50 (2H, m), 3.93-4.08 (2H, m), 5.73 (1H, d,J=3 Hz), 7.16 (1H, d, J=2 Hz), 7.37 (1H, d, J=2 Hz), 7.47 (1H, d, J=3Hz), 8.15 (1H, s), 8.16 (1H, br s).

PREPARATION 36

The following compound was obtained according to a similar manner tothat of Preparation 21.

1-(1-Methoxycarbonyl-1-methylethyl)-1H-imidazo-[1,2-b]pyrazole

NMR (DMSO-d₆, δ) : 1.79 (6H, s), 3.64 (3H, s), 5.65 (1H, d, J=2 Hz),7.30 (1H, d, J=3 Hz), 7.47 (1H, d, J=3 Hz), 7.59 (1H, d, J=2 Hz).

PREPARATION 37

To a solution of 1-ethoxycarbonylmethyl-1H-imidazo-[1,2-b]pyrazole (7.0g) in ethanol (35 ml) was added 50% dimethylamine aqueous solution (17ml). The mixture was stirred at room temperature for 5 hours. Thereaction mixture was evaporated in vacuo. The resultant crude powder wassubjected to column chromatography on silica gel using a mixture ofethyl acetate and methanol as an eluent. Fractions containing the objectcompound were combined and evaporated in vacuo. The resultantprecipitate was collected and washed with diisopropyl ether to give1-(N,N-dimethylcarbamoylmethyl)-1H-imidazo[1,2-b]-pyrazole (1.6 g).

IR (Nujol) : 3100, 1660, 1600, 1500 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.84 (3H, s), 3.01 (3H, s), 4.90 (2H s), 5.61 (1H, d,J=3 Hz), 7.03 (1H, br s), 7.43 (1H, br s), 7.50 (1H, d, J=3 Hz).

PREPARATION 38

To a solution of hydrazinoacetaldehyde diethyl acetal (52.6 g) inethanol (110 ml) was added dropwise a solution ofethoxymethylenemalononitrile (41.5 g) in ethanol (420 ml) at roomtemperature. The mixture was stirred at ambient temperature for 24hours. The reaction mixture was evaporated in vacuo. To the residue wasadded diethyl ether (400 ml) and the resultant precipitate was filteredoff. The filtrate was subjected to column chromatography on silica gelusing a mixture of ethyl acetate and hexane (2:3) as an eluent.Fractions containing the object compound were combined and evaporated togive 5-amino-4-cyano-1-(2,2-diethoxyethyl)pyrazole (23.0 g).

IR (Nujol) : 3400, 3300, 3150, 2200, 1650, 1565, 1530 cm⁻¹.

NMR (DMSO-d₆, δ) : 1.05 (6H, t, J=7 Hz), 3.33-3.48 (2H, m), 3.55-3.70(2H, m), 3.98 (2H, d, J=6 Hz), 4.78 (1H, t, J=6 Hz), 6.54 (2H, br s),7.55 (1H, s).

PREPARATION 39

A solution of 5-amino-4-cyano-1-(2,2-diethoxyethyl)-pyrazole (23 g) in1N hydrochloric acid (205 ml) was heated at 60-70° C. The mixture wasstirred for 0.5 hour at the same condition. The reaction mixture wascooled under ice-water and the resultant solid was collected byfiltration, washed with ice-water and dried over phosphorus pentoxide invacuo to the crude product. The product was crystallized from ethanol(400 ml) to give 7-cyano-1H-imidazo[1,2-b]pyrazole (12.4 g).

IR (Nujol) : 2210, 1620 cm⁻¹.

NMR (DMSO-d₆, δ) : 7.42 (1H, dd, J=1Hz, 2 Hz), 7.82 (1H, d, J=2 Hz),8.09 (1H, d, J=1Hz), 12.38 (1H, br s).

PREPARATION 40

7-Cyano-1H-imidazo[1,2-b]pyrazole (3 g) was added to conc. sulfuric acidunder ice-cooling. The mixture was stirred at room temperature for 45minutes. The reaction mixture was cooled at 0°-5° C. and carefullypoured into ice water (30 ml). The aqueous solution was neutralized withconc. ammonium hydroxide solution and stirred for 1 hour underice-cooling. The precipitate was collected, washed with cold water anddried over phosphorus pentoxide in vacuo to give7-carbamoyl-1H-imidazo[1,2-b]pyrazole (3.45 g).

IR (Nujol) : 3100-3500, 1690,1650, 1620 cm⁻¹.

NMR (DMSO-d₆, δ) : 7.05 (2H, br s), 7.20 (1H, dd, J=1Hz, 2 Hz), 7.61(1H, d, J=2 Hz), 8.02 (1H, d, J=1Hz), 10.49 (1H, br s).

PREPARATION 41

The following compound was obtained according to a similar manner tothat of Preparation 40.

1-Methyl-7-carbamoyl-1H-imidazo[1,2-b]pyrazole

IR (Nujol) : 3350, 3150, 1680, 1620, 1600 cm⁻¹.

NMR (DMSO-d₆, δ) : 4.00 (3H, s), 7.22 (1H, dd, J=1Hz, 2 Hz), 7.63 (1H,d, J=2 Hz), 8.05 (1H, d, J=1Hz).

PREPARATION 42

A solution of 5-amino-4-carboxy-1-(2,2-diethoxyethyl)pyrazole (50 g) in80% trifluoroacetic acid aqueous solution (250 ml) was stirred at roomtemperature for two days. The reaction mixture was evaporated in vacuo.The resultant solid was washed with cold water, collected by filtrationand dried over phosphorus pentoxide in vacuo to give7-carboxy-1H-imidazo[1,2-b]-pyrazole (17.10 g).

NMR (DMSO-d₆, δ) : 7.27 (1H, s), 7.70 (1H, s), 7.89 (1H, s), 12.04 (1H,br s).

PREPARATION 43

To a solution of 5-amino-1-(2,2-diethoxyethyl-4-carboxypyrazole (50 g)in N,N-dimethylformamide (150 ml) was added potassium carbonate (28.4 g)under ice-cooling. After stirring at 5° C. for 30 minutes, to themixture was added methyl iodide (25.6 ml). The mixture was stirred atthe same condition for 3 hours. The reaction mixture was poured into amixture of ethyl acetate (1 l) and water (1 l). The separated organiclayer was washed with water and brine and dried over magnesium sulfate.The solvent was evaporated in vacuo to give5-amino-1-(2,2-diethoxyethyl)-4-methoxycarbonylpyrazole (43.02 g).

IR (Nujol) : 2900-3000, 1680, 1630 cm⁻¹.

NMR (DMSO-d₆, δ) : 1.05 (6H, t, J=7 Hz), 3.33-3.70 (4H, m), 4.00 (2H, d,J=6 Hz), 4.79 (1H, t, J=6 Hz), 6.25 (2H, br s), 7.48 (1H, s).

PREPARATION 44

The following compound was obtained according to a similar manner tothat of Preparation 42.

7-Methoxycarbonyl-1H-imidazo[1,2-b]pyrazole

IR (Nujol) : 1680, 1620, 1550 cm⁻¹.

NMR (DMSO-d₆, δ) : 3.76 (3H, s), 7.32 (1H, dd, J=1Hz, 2 Hz), 7.74 (1H,d, J=2 Hz), 7.95 (1H, s), 12.12 (1H, br s).

PREPARATION 45

A solution of 1-methyl-7-methoxycarbonyl-1H-imidazo[1,2-b]pyrazole (5.0g) in 4N-sodium hydroxide aqueous solution (14 ml) was refluxed for 1hour. The reaction mixture was cooled with ice-bath and adjusted to pH3.0 with 6N hydrochloric acid. The resultant solid was collected byfiltration, washed with cold water and dried over phosphorus pentoxidein vacuo to give 7-carboxy-1-methyl-1H-imidazo[1,2-b]pyrazole (4.42 g).

IR (Nujol) : 1660, 1600 cm⁻¹.

NMR (DMSO-d₆, δ) : 3.97 (3H, s), 7.29 (1H, d, J=2 Hz), 7.72 (1H, d, J=2Hz), 7.89 (1H, s).

PREPARATION 46

To a solution of 7-amino-1H-imidazo[1,2-b]pyrazole dihydrochloride (10g) in pyridine (100 ml) was added dropwise acetyl chloride (7.3 ml)under ice-cooling. The mixture was stirred at room temperature for twohours. The reaction mixture was poured into ice water (200 ml) andextracted with a mixture of ethyl acetate (200 ml) and tetrahydrofuran(300 ml). The organic layer was dried over magnesium sulfate and thesolvent was evaporated to give1-acetyl-7-acetylamino-1H-imidazo[1,2-b]pyrazole (3.13 g).

IR (Nujol) : 3350, 1680, 1660 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.01 (3H, s), 2.53 (3H, s), 7.70 (1H, d, J=2 Hz),7.82 (1H, d, J=2 Hz), 7.88 (1H, s), 9.15 (1H, br s).

PREPARATION 47

Triphenylmethyl chloride (154.98 g) was added to a solution oftriethylamine (154.97 ml) and 1-methoxycarbonylmethyl-5-aminopyrazole(71.88 g) in tetrahydrofuran (215.64 ml) and the mixture was stirred forthree hours at ambient temperature. The reaction mixture was added to amixture of water (300 ml) and ethyl acetate (200 ml). The organic layerwas separated and dried over magnesium sulfate The magnesium sulfate wasfiltered off, and the filtrate was evaporated under reduced pressure togive 1-methoxycarbonylmethyl-5-triphenylmethylaminopyrazole.

IR (Nujol) : 1720, 1550, 750, 700 cm⁻¹.

NMR (DMSO-d₆, δ) : 3.72 (3H, s), 4.52 (1H, d, J=1.9 Hz), 4.97 (2H, s),6.54 (1H, s), 6.87 (1H, d, J=1.9 Hz), 7.18-7.33 (15H, m).

PREPARATION 48

4N Sodium hydroxide aqueous solution (125.79 ml) was added to a solutionof 1-methoxycarbonylmethyl-5-triphenylmethylaminopyrazole (100 g) indioxane (100 ml) and the mixture was stirred for three hours at ambienttemperature. The reaction mixture was added to a mixture of ethylacetate (300 ml) and tetrahydrofuran (300 ml), and 1N hydrochloric acidwas added thereto to adjust to pH 3. The organic layer was separated anddried over magnesium sulfate. The magnesium sulfate was filtered off,and the filtrate was evaporated under reduced pressure to give1-carboxymethyl-5-triphenylmethylaminopyrazole.

IR (Nujol) : 1700, 1230, 755, 740, 690 cm⁻¹.

NMR (DMSO-d₆, δ) : 4.51 (1H, d, J=1.9 Hz), 4.85 (2H, s), 6.49 (1H, s),6.84 (1H, d, J=1.9 Hz), 7.15-7.41 (15H, m).

PREPARATION 49

A solution of methyllithium in diethyl ether (250 ml) was added to asolution of 1-carboxymethyl-5-triphenylmethylaminopyrazole (25.95 g) intetrahydrofuran (400 ml) under ice-cooling and the mixture was stirredfor hours at ambient temperature. The reaction mixture was added to amixture of ice-cold water (500 ml) and diethyl ether (500 ml). Theorganic layer was separated and dried over magnesium sulfate. Themagnesium sulfate was filtered off, and the filtrate was evaporatedunder reduced pressure to give1-acetylmethyl-5-triphenylmethylaminopyrazole.

IR (Nujol) : 1720, 1540, 750, 700 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.01 (3H, s), 4.58 (1H, d, J=1.9 Hz), 4.92 (2H, s),6.47 (1H, s), 6.90 (1H, d, J=1.9 Hz), 7.18-7.31 (15H, m).

PREPARATION 50

The following compound was obtained according to a similar manner tothat of Preparation 3.

1-Formyl-2-methyl-1H-imidazo[1,2-b]pyrazole

IR (Nujol) : 1680, 1550, 930, 740 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.46 (3H, s), 6.21 (1H, d, J=1.9 Hz), 7.61 (1H, s),7.61 (1H, d, J=1.9 Hz), 9.03 (1H, s).

PREPARATION 51

To a solution of 1H-imidazo[1,2-b]pyrazole (2 g) in tetrahydrofuran (20ml) were added N,N-dimethylcarbamoyl chloride (3.8 ml) and triethylamine(6.2 ml) at 20° C. under stirring. After stirring, the reaction mixturewas poured into a mixture of ethyl acetate (30 ml) and cold water (50ml). The ethyl acetate layer was separated, washed with water and asaturated aqueous solution of sodium chloride, dried over magnesiumsulfate and evaporated in vacuo to give1-(N,N-dimethylcarbamoyl)-1H-imidazo[1,2-b]pyrazole (3.0 g).

NMR [DMSO-d₆, δ) : 3.00 (6H, s), 5.94 (1H, d, J=3 Hz), 7.49 (1H, d, J=2Hz), 7.62 (1H, d, J=2 Hz), 7.79 (1H, d, J=3 Hz).

PREPARATION 52

To a solution of 1H-imidazo[1,2-b]pyrazole (2.5 g) in tetrahydrofuran(10 ml) was added acetic anhydride (3.1 ml) under stirring at 35° C. andthe mixture was stirred for 2 hours at the same temperature. Thereaction mixture was evaporated in vacuo to give1-acetyl-1H-imidazo[1,2-b]-pyrazole (2.7 g).

IR (Nujol) : 1710, 1585, 1540 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.55 (3H, s), 6.19 (1H, d, J=3 Hz), 7.66 (1H, d, J=2Hz), 7.10 (1H, br s), 7.78 (1H, d, J=3 Hz).

PREPARATION 53

The following compounds were obtained according to a similar manner tothat of Preparation 5.

(1) Benzhydryl7β-(t-butoxycarbonylamino)-3-[1-acetyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

NMR (DMSO-d₆, δ) : 1.41 (9H, s), 2.71 (3H, s), 3.30-3.50 (2H, m), 5.15(1H, d, J=5 Hz), 5.44 and 5.55 (2H, ABq, J=18 Hz), 5.50-5.70 (1H, m),6.92 (1H, s), 6.97 (1H, d, J=3 Hz), 7.22-7.53 (10H, m), 8.07 (1H, d,J=10 Hz), 8.22 (1H, d, J=2 Hz), 8.28 (1H, m), 8.40 (1H, d, J=3 Hz).

(2) Benzhydryl7β-[t-butoxycarbonylamino)-3-[1-(N,N-dimethylcarbamoyl)-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

NMR (DMSO-d₆, δ) : 1.35-1.51 (9H, m), 3.10 (6H, s), 3.20-3.68 (2H, m),5.16 (1H, d, J=5 Hz), 5.39 and 5.48 (2H, ABq, J=14 Hz), 5.66 (1H, dd,J=5 Hz, 8 Hz), 6.77 (1H, d, J=3 Hz), 6.95 (1H, s), 7.08-7.60 (10H, m),8.08 (1H, d, J=2 Hz), 8.15 (1H, d, J=2 Hz), 8.33 (1H, d, J=3 Hz).

(3) Benzhydryl7β-(t-butoxycarbonylamino)-3-[1,2-dimethyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

IR (Nujol) : 1780, 1710, 1600 cm⁻¹.

NMR (DMSO-d₆, δ) : 1.40 (9H, s), 2.30 (3H, s), 3.37 (2H, br s), 3.70(3H, s), 5.12 (1H, d, J=5 Hz), 5.20 and 5.40 (12H, ABq, J=15 Hz), 5.56(1H, dd, J=8 Hz, 5 Hz), 6.63 (1H, d, J=3 Hz), 6.90 (1H, s), 7.10-7.50(10H, m), 7.57 (1H, s), 8.01 (1H, d, J=3 Hz).

(4) Benzhydryl7β-(t-butoxycarbonylamino)-3-[1-acetyl-7-acetylamino-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

NMR (DMSO-d₆, δ) : 1.41 (9H, s), 2.10 (3H, s), 2.53 (3H, s), 3.42 (2H,br s), 5.15 (1H, d, J=5 Hz), 5.13-5.30 (2H, m), 5.63 (1H, dd, J=5 Hz, 8Hz), 6.94 (1H, s), 7.29-7.54 (10H, m), 7.60 (1H, br s), 7.70 (1H, d, J=2Hz), 8.04 (1H, s), 8.10 (1H, d, J=8 Hz).

(5) Benzhydryl7β-(t-butoxycarbonylamino)-3-[7-carboxy-1-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

NMR (DMSO-d₆, δ) : 1.41 (9H, s), 3.60 (2H, br s), 4.01 (3H, s), 5.15(1H, d, J=5 Hz), 5.30 and 5.50 (2H, ABq, J=15 Hz), 5.63 (1H, dd, J=5 Hz,8 Hz), 6.73 (1H, s), 7.20-7.45 (10H, m), 7.80 (1H, br s), 7.86 (1H, brs), 8.02 (1H, d, J=8 Hz), 8.63 (1H, s).

(6) Benzhydryl7β-(t-butoxycarbonylamino)-3-[1-methyl-7-methoxycarbonyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

NMR (DMSO-d₆, δ) : 1.41 (9H, s), 3.48 (2H, br s), 3.94 (3H, s), 4.22(3H, s), 5.15 (1H, d, J=5 Hz), 5.34 and 5.55 (2H, ABq, J=16 Hz), 5.65(1H, dd, J=5 Hz, 8 Hz), 6.92 (1H, s), 7.27-7.50 (10H, m), 7.83 (1H, brs), 7.91 (1H, d, J=2 Hz), 8.08 (1H, d, J=8 Hz), 8.74 (1H, s).

(7) Benzhydryl7β-(t-butoxycarbonylamino)-3-[1-methyl-7-carbamoyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

IR (Nujol) : 1780, 1700, 1650 cm⁻¹.

NMR (DMSO-d₆, δ) : 1.41 (9H, s), 3.48 (2H, br s), 4.09 (3H, s), 5.14(1H, d, J=5 Hz), 5.34 and 5.48 (2H, ABq, J=16 Hz), 5.66 (1H, dd, J=5, 8Hz), 6.94 (1H, s), 7.22-7.60 (10H, m), 7.62 (1H, br s), 7.95 (1H, br s),8.06 (1H, d, J=8 Hz), 8.64 (1H, s).

(8) Benzhydryl7β-[t-butoxycarbonylamino)-3-[7-carbamoyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

NMR (DMSO-d₆, δ) : 1.41 (9H, s), 3.51 (2H, br s), 5.16 (1H, d, J=5 Hz),5.34 and 5.48 (2H, ABq, J=15 Hz), 5.66 (1H, dd, J=5, 8 Hz), 7.05 (1H,s), 7.26-7.50 (10H, m), 7.60 (1H, br s), 7.95 (1H, br s), 8.02 (1H, d,J=8 Hz), 8.64 (1H, s).

(9) Benzhydryl7β-(t-butoxycarbonylamino)-3-[1-(N,N-dimethylcarbamoylmethyl)-5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylateiodide

IR (Nujol) : 1780, 1710, 1650 cm⁻¹.

NMR (DMSO-d₆, δ) : 1.41 (9H, s), 2.88 (3H, s), 3.06 (3H, s), 3.44 (2H,br s), 5.19 (1H, d, J=5 Hz), 5.29 (2H, s), 5.28 and 5.46 (2H, ABq, J=15Hz), 5.65 (1H, dd, J=5, 8 Hz), 6.63 (1H, d, J=3 Hz), 6.97 (1H, s),7.26-7.64 (10H, m), 7.64 (1H, d, J=2 Hz), 7.86 (1H, d, J=2 Hz), 8.07(1H, d, J=8 Hz), 8.14 (1H, d, J=3 Hz).

(10) Benzhydryl7β-(t-butoxycarbonylamino-3-[1-(1-carbamoyl-1-methylethyl)-5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylateiodide

NMR (DMSO-d₆, δ) : 1.40 (9H, s), 1.84 (6H, s), 3.37 (2H, br s), 5.17(1H, d, J=5 Hz), 5.29 and 5.43 (2H, ABq, J=15 Hz), 5.62 (1H, dd, J=5 Hz,8 Hz), 6.68 (1H, d, J=3 Hz), 6.94 (1H, s), 7.20-7.60 (10H, m), 7.85 (1H,br s), 7.99 (1H, br s), 8.07 (1H, d, J=8 Hz), 8.13 (1H, d, J=3 Hz).

(11) Benzhydryl7β-(t-butoxycarbonylamino)-3-[1-(2-formylaminoethyl)-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

IR (Nujol) 1780, 1710, 1570 cm⁻¹.

NMR (DMSO-d₆, δ) : 1.40 (9H, s), 3.37 (2H, br s), 3.51-3.63 (2H, m),4.23 (2H, t, J=6 Hz), 5.13 (1H, d, J=5 Hz), 5.33 and 5.49 (2H, ABq, J=16Hz), 5.64 (1H, dd, J=5, 8 Hz), 6.73 (1H, d, J=3 Hz), 6.96 (1H, s),7.18-7.53 (10H, m), 7.76 (1H, br s), 7.80 (1H, br s), 7.94 (1H, s), 8.08(1H, d, J=8 Hz), 8.18 (1H, d, J=3 Hz).

(12) Benzhydryl7β-(t-butoxycarbonylamino)-3-[1-carbamoylmethyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

(13) Benzhydryl7β-(t-butoxycarbonylamino)-3-[1,7-dimethyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

IR (Nujol) : 1775, 1710, 1655, 1605 cm⁻¹.

NMR (DMSO-d₆, δ) : 1.42 (9H, s), 2.26 (3H, s), 3.41 (2H, s), 3.89 (3H,s), 5.09 and 5.35 (2H,

ABq, J=16 Hz), 5.16 (1H, d, J=5 Hz), 5.58 (1H, dd, J=8 Hz, 5 Hz), 6.92(1H, s), 7.05-7.46 (10H, m), 7.62 (1H, m), 7.72 (1H, m), 7.83 (1H, m),7.95 (1H, d, J=8 Hz).

PREPARATION 54

The following compounds were obtained according to a similar manner tothat of Preparation 27.

(1)7β-Amino-3-[1,7-dimethyl-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

IR (Nujol) : 1785, 1670 cm⁻¹.

NMR (D₂ O, δ) : 2.36 (3H, s), 3.26 and 3.51 (2H, ABq, J=18 Hz), 3.93(3H, s), 5.16 (1H, d, J=5 Hz), 5.27 (1H, d, J=5 Hz), 5.30 (2H, s), 7.35(1H, m), 7.75 (2H, m).

(2) 7β-Amino-3-[1-(1-carbamoyl-1-methylethyl)-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatetrifluoroacetate)

NMR (DMSO-d₆, δ) : 1.85 (6H, s), 3.39 and 3.59 (2H, ABq, J=18 Hz), 5.26(2H, s), 5.48 (2H, s), 6.72 (1H, d, J=3 Hz), 7.54 (1H, br s), 7.58 (1H,br s), 7.92 (1H, d, J=2 Hz), 8.20 (1H, d, J=2 Hz), 8.28 (1H, d, J=3 Hz).

(3)7β-Amino-3-[1-methyl-7-methoxycarbonyl-5-(1H-imidazo-[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

NMR (DMSO-d₆, δ) : 3.45 and 3.58 (2H, ABq, J=18 Hz), 3.89 (3H, s), 4.08(3H, s), 5.23 and 5.28 (2H, ABq, J=5 Hz), 5.54 (2H, br s), 7.88 (1H, d,J=2 Hz), 8.22 (1H, d, J=2 Hz), 8.91 (1H, s).

(4)7β-Amino-3-[7-carboxy-1-methyl-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

NMR (DMSO-d₆, δ) : 3.47 and 3.60 (2H, ABq, J=18 Hz), 4.09 (3H, s),5.21-5.30 (2H, m), 5.52 (2H, br s), 7.86 (1H, br s), 8.19 (1H, br s),8.78 (1H, s).

(5)7β-Amino-3-[1-acetyl-7-acetylamino-5-{1H-imidazo-[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

NMR (DMSO-d₆, δ) : 2.00 (3H, s), 2.11 (3H, s), 3.39 and 3.53 (2H, ABq,J=18 Hz), 5.10 (1H, d, J=5 Hz), 5.23 (2H, br s), 5.61 (1H, dd, J=5 Hz, 8Hz), 7.70 (1H, br s), 8.06 (1H, d, J=2 Hz), 8.23 (1H, d, J=8 Hz), 8.68(1H, s).

(6)7β-Amino-3-[2-methyl-5-[1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylatetris(trifluoroacetate)

IR (Nujol) : 1780, 1200, 720 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.40 (3H, s), 3.50 (2H, br s), 5.05 (1H, m), 5.20(2H, s), 5.50 (1H, m), 5.53 (1H, d, J=3 Hz), 7.76 (1H, s), 8.15 (1H, d,J=3 Hz).

(7)7β-Amino-3-[1,2-dimethyl-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylatetris(trifluoroacetate)

IR (Nujol) : 1780, 1660, 1600 cm⁻¹.

NMR (DMSO-d +D₂ O, δ) : 2.36 (3H, s), 3.40 (2H, m), 3.70 (3H, s), 5.16(2H, m), 5.36 (2H, s), 6.62 (1H, d, J=3 Hz), 7.76 (1H, s), 8.06 (1H, d,J=3 Hz).

(8)7β-Amino-3-[1-(N,N-dimethylcarbamoyl)-5-[1H-imidazo-[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

NMR (DMSO-d₆, δ): 3.10 (6H, s), 3.40-3.60 (2H, m), 5.21-5.33 (2H, m),5.38-5.61 (2H, m), 6.81 (1H, d, J=3 Hz), 8.13 (1H, d, J=2 Hz), 8.31 (1H,d, J=2 Hz), 8.45 (1H, d, J=2 Hz).

PREPARATION 55

A solution of benzhydryl7β-(t-butoxycarbonylamino)-3-[1-carbamoylmethyl-5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylateiodide (4.7 g) in a mixture of formic acid (18.8 ml) and conc.hydrochloric acid (1.0 ml) was stirred at room temperature for 2 hours.The reaction mixture was poured into a mixture of acetone (140 ml) andethyl acetate (280 ml). The resultant precipitate was collected byfiltration, washed with diisopropyl ether and dried over phosphoruspentoxide in vacuo to give7β-amino-3-[1-carbamoylmethyl-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylatedihydrochloride (2.73 g).

NMR (DMSO-d₆, δ) : 3.42, 3.58 (2H, ABq, J=18 Hz), 4.97 (2H, s), 5.25(2H, s), 5.54 (2H, s), 6.73 (1H, d, J=3 Hz), 7.49 (1H, s), 7.81 (1H, d,J=2 Hz), 7.96 (1H, s), 8.16 (1H, d, J=2 Hz), 8.36 (1H, d, J=3 Hz).

PREPARATION 56

The following compounds were obtained according to a similar manner tothat of Preparation 55.

(1)7β-Amino-3-[1-(2-formylaminoethyl)-5-(1H-imidazo-[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatedihydrochloride

IR (Nujol) : 1780, 1730, 1710, 1670, 1600 cm⁻¹.

NMR (DMSO-d₆, δ) : 3.37 and 3.49 (2H, ABq, J=18 Hz), 3.34 (2H, t, J=6Hz), 4.29 (2H, t, J=6 Hz), 5.23 (2H, s), 5.53 (2H, s), 6.80 (1H, d, J=3Hz), 7.85 (1H, br s), 7.94 (1H, s), 8.11 (1H, d, J=br s), 8.34 (1H, d,J=3 Hz), 8.39 (1H, br s).

(2)7β-Amino-3-[1-(N,N-dimethylcarbamoylmethyl)-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatedihydrochloride

NMR (DMSO-d₆, δ) : 2.88 (3H, s), 3.06 (3H, s), 3.42 and 3.58 (2H, ABq,J=18 Hz), 5.23 and 5.27 (2H, ABq, J=5 Hz), 5.35 (2H, s), 5.55 (2H, s),6.70 (1H, d, J=3 Hz), 7.74 (1H, br s), 8.18 (1H, br s), 8.36 (1H, d, J=3Hz).

(3)7β-Amino-3-[7-carbamoyl-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylatedihydrochloride

NMR (DMSO-d₆, δ) : 3.56 and 3.71 (2H, ABq, J=18 Hz), 5.28 (2H, br s),5.54 (2H, s), 7.81 (1H, br s), 8.23 (1H, br s), 8.94 (1H, s).

(4)7β-Amino-3-[1-methyl-7-carbamoyl-5-[1H-imidazo-[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatedihydrochloride

IR (Nujol) : 1780, 1700, 1660, 1600 cm⁻¹.

NMR (DMSO-d₆, δ) : 3.56 and 3.73 (2H, ABq, J=18 Hz), 4.12 (3H, s), 5.26and 5.31 (2H, ABq, J=5 Hz), 5.54 (2H, s), 7.86 (1H, br s), 8.28 (1H, brs), 9.07 (1H, s).

(5)7β-Amino-3-[1-acetyl-5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylatedihydrochloride

NMR (D₂ O, δ) : 2.80 (3H, s), 3.30-3.81 (2H, m), 5.10-5.70 (4H, m), 6.95(1H, d, J=3 Hz), 7.95-8.25 (2H, m), 8.35 (1H, d, J=3 Hz).

PREPARATION 57

To a suspension of7β-amino-3-[1-acetyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatedihydrochloride (1 g) in methanol (10 ml) was added hydrochloric acid(0.65 ml) under stirring at 25° C. The mixture was stirred for 3 hoursat 30° C. The reaction mixture was poured into ethyl acetate (400 ml).The resultant precipitates were collected by filtration to give7β-amino-3-[5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatetrihydrochloride (880 mg).

IR (Nujol) 1780, 1705, 1600, 1510 cm⁻¹.

NMR (D₂ O, δ) : 3.25-3.60 (2H, m), 5.10-5.38 (2H, m), 5.40-5.70 (2H, m),6.48 (1H, d, J=3 Hz), 7.58 (1H, d, J=2 Hz), 7.85 (1H, d, J=2 Hz), 8.03(1H, J=3 Hz).

PREPARATION 58

To a solution of 1-(2-oxopropyl)-5-triphenylmethylaminopyrazole (0.75 g)in methanol was added conc. hydrochloric acid (0.75 ml). The mixture wasstirred for 2 hours. The reaction mixture was added to a mixture ofethyl acetate, tetrahydrofuran and ice-cold water, and the mixture wasadjusted to pH 8 with sodium bicarbonate. The organic layer wasseparated and dried over magnesium sulfate. The magnesium sulfate wasfiltered off, and the filtrate was evaporated under reduced pressure.The residue was pulverized with diisopropyl ether to give2-methyl-1H-imidazo[1,2-b]pyrazole.

PREPARATION 59

Benzhydryl7β-(t-butoxycarbonylamino)-3-chloromethyl-3-cephem-4-carboxylate (3.91g) was added to N,N-dimethylformamide (4 ml) under stirring. Sodiumiodide (1.14 g) and 1-formyl-2-methyl-1H-imidazo[1,2-b]-pyrazole (1.7 g)were added to the mixture. The mixture was stirred for 12 hours atambient temperature. The reaction mixture was added to a mixture ofethyl acetate (230 ml) and ice-cold water (115 ml). The organic layerwas separated, washed with brine and dried over magnesium sulfate. Themagnesium sulfate was filtered off, and the filtrate was evaporatedunder reduced pressure. The residue was pulverized with diisopropylether to give benzhydryl7β-(t-butoxycarbonylamino)-3-[2-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide.

IR (Nujol) : 1780, 1710, 1160 cm⁻¹.

NMR (DMSO-d₆, δ) : 1.45 (9H, s), 2.33 (3H, s), 3.35 (2H, br s), 5.14(1H, d, J=5 Hz), 5.30 (2H, m), 5.60 (1H, dd, J=8 Hz, 5 Hz), 6.50 (1H, d,J=3 Hz), 6.92 (1H, s), 7.1-7.6 (10H, m), 7.90 (1H, s), 7.95 (1H, d, J=8Hz), 8.01 (1H, d, J=3 Hz).

EXAMPLE 7

The following compounds were obtained according to similar manners tothose of Example 1, 2 and 5.

(1)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[1,7-dimethyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 3280, 3100, 1760, 1660, 1605cm⁻¹.

NMR (DMSO-d₆, δ) : 2.33 (3H, s), 2.90 and 3.35 (2H, ABq, J=17 Hz), 3.80(3H, s), 3.89 (3H, s), 4.98 (1H, d, J=5 Hz), 5.14 and 5.45 (2H, ABq,J=15 Hz), 5.58 (1H, dd, J=8 Hz, 5 Hz), 6.66 (1H, s), 7.15 (2H, br s),7.61 (1H, m), 8.08 (1H, m), 8.85 (1H, d, J=3 Hz), 9.45 (1H, d, J=8 Hz).

(2)7β-[2-[5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1,7-dimethyl-5-(1H-imidazo-[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn

IR (Nujol) : 1775, 1675, 1630, 1605cm⁻¹.

NMR (DMSO-d₆, δ) : 2.31 (3H, s), 2.78 and 3.31 (2H, ABq, J=18 Hz), 3.88(6H, s), 4.96 (1H, d, J=5 Hz), 5.13 and 5.44 (2H, ABq, J=16 Hz), 5.59(1H, dd, J=8 Hz, 5 Hz), 7.61 (1H, m), 8.08 (3H, m), 8.85 (1H, d, J=3Hz), 9.41 (1H, d, J=8 Hz).

(3)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[6-methyl-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) 1760, 1670, 1600 cm⁻¹.

NMR (D₂ O, δ) : 1.31 (3H, t, J=7 Hz), 2.51 (3H, s), 3.13 and 3.33 (2H,ABq, J=18 Hz), 4.32 (2H, q, J=7 Hz), 5.16 (1H, d, J=5 Hz), 5.21 (2H, brs), 5.82 (1H, d, J=5 Hz), 6.17 (1H, s), 7.32 (1H, br s), 7.80 (1H, brs).

(4)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[1-carbamoylmethyl-5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylate(syn isomer)

IR [Nujol) : 1770, 1680, 1600 cm⁻¹.

NMR (DMSO-d₆, δ) : 3.30 (2H, br s), 3.80 (3H, s), 4.90 (2H, s), 5.02(1H, d, J=5 Hz), 5.22 and 5.55 (2H, ABq, J=15 Hz), 5.60 (1H, dd, J=5 Hz,8 Hz), 6.55 (1H, d, J=3 Hz), 6.67 (1H, s), 7.13 (2H, br s), 7.37 (1H, brs), 7.65 (1H, br s), 7.83 (1H, br s), 8.31 (1H, d, J=3 Hz), 8.98 (1H, brs), 9.46 (1H, d, J=8 Hz).

(5)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1-carbamoylmethyl-5-[1H-imidazo-[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn

IR (Nujol) : 3300, 3100, 1775, 1680, 1600 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.80 and 3.41 (2H, ABq, J=18 Hz), 3.85 (3H, s), 4.90(2H, br s), 4.99 (1H, d, J=5 Hz), 5.22 and 5.58 (2H, ABq, J=13 Hz), 5.62(1H, dd, J=5 Hz, 8 Hz), 6.55 (1H, d, J=3 Hz), 7.37 (1H, br s), 7.64 (1H,d, J=2 Hz), 7.89 (1H, br s), 8.10 (2H, br s), 8.32 (1H, d, J=3 Hz), 8.97(1H, d, J=2 Hz), 9.45 (1H, d, J=8 Hz).

(6)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[1-carbamoylmethyl-5-(1H-imidazo-[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1765, 1680, 1600, 1520 cm⁻¹.

NMR (DMSO-d₆, δ) : 1.20 (3H, t, J=7 Hz), 2.80 and 3.34 (2H, ABq, J=17Hz), 4.12 (2H, q, J=7 Hz), 4.89 (2H, s), 5.02 (1H, d, J=5 Hz), 5.23 and5.54 (2H, ABq, J=15 Hz), 5.64 (1H, dd, J=5 Hz, 8 Hz), 6.59 (1H, d, J=3Hz), 7.47 (1H, s), 7.69 (1H, br s), 7.86 (1H, s), 8.16 (2H, s), 8.35(1H, d, J=3 Hz), 9.07 (1H, d, J=2 Hz), 9.52 (1H, d, J=8 Hz).

(7)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1-(2-formylaminoethyl)-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn

IR (Nujol) : 3350, 1770, 1660, 1600 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.80 and 3.32 (2H, ABq, J=18 Hz), 3.40-3.67 (2H, m),3.87 (3H, s), 4.10-4.40 (2H, m), 4.97 (1H, d, J=5 Hz), 5.25 and 5.49(2H, ABq, J=13 Hz), 5.62 (1H, dd, J=5 Hz, 8 Hz), 6.62 (1H, d, J=3 Hz),7.72 (1H, br s), 7.92 (1H, br s), 8.09 (2H, br s), 8.32 (1H, d, J=3 Hz),8.85 (1H, br s), 9.44 (1H, d, J=8 Hz).

(8)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1-(1-carbamoyl-1-methylethyl)-5-(1H-imidazo-[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn

IR (Nujol) : 1760, 1680, 1610 cm⁻¹.

NMR (DMSO-d₆, δ) : 1.85 (6H, s), 2.81 and 3.32 (2H, ABq, J=18 Hz), 3.87(3H, s), 5.00 (1H, d, J=5 Hz), 5.20 and 5.54 (2H, ABq, J=15 Hz), 5.59(1H, dd, J=5 Hz, 8 Hz), 6.54 (1H, d, J=3 Hz), 7.40 (1H, br s), 7.51 (1H,br s), 7.79 (1H, d, J=1Hz), 8.08 (2H, br s), 8.32 (1H, d, J=3 Hz), 9.05(1H, d, J=1Hz), 9.42 (1H, d, J=8 Hz).

(9)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[1-(1-carbamoyl-1-methylethyl)-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1770, 1670, 1610 cm⁻¹.

NMR (DMSO-d₆, δ) : 1.84 (6H, s), 2.80 and 3.37 (2H, ABq, J=18 Hz), 3.76(3H, s), 4.96 (1H, d, J=5 Hz), 5.17 and 5.59 (2H, ABq, J=15 Hz), 5.53(1H, dd, J=5 Hz, 8 Hz), 6.49 (1H, d, J=3 Hz), 6.61 (1H, s), 7.08 (2H, brs), 7.37 (1H, br s), 7.45 (1H, br s), 7.73 (1H, br s), 8.27 (1H, d, J=3Hz), 8.97 (1H, br s), 9.40 (1H, d, J=8 Hz).

(10)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1-(N,N-dimethylcarbamoylmethyl)-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1770, 1650 1600 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.88 (3H, s), 3.06 (3H, s), 3.43 (2H, br s), 3.87(3H, s), 5.01 (1H, d, J=5 Hz), 5.24 (2H, s), 5.22 and 5.57 (2H, ABq,J=15 Hz), 5.60 (1H, dd, J=5 Hz, 8 Hz), 6.51 (1H, d, J=3 Hz), 7.57 (1H,br s), 8.09 (2H, br s), 8.31 (1H, d, J=3 Hz), 9.37 (1H, br s), 9.44 (1H,d, J=8 Hz).

(11)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[7-carbamoyl-5-(1H-imidazo-[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1780, 1760, 1660, 1610 cm

NMR (DMSO-d₆, δ) : 3.08 and 3.43 (2H, ABq, J=18 Hz), 3.89 (3H, s), 5.06(1H, d, J=5 Hz), 5.35 (2H, br s), 5.72 (1H, dd, J=5 Hz, 8 Hz), 7.43 (2H,br s), 7.50 (1H, br s), 8.07 (2H, br s), 8.25 (1H, br s), 8.50 (1H, s),9.48 (1H, d, J=8 Hz).

(12)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1-methyl-7-carbamoyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

NMR (DMSO-d₆, δ) : 3.52 (2H, br s), 3.88 (3H, s), 4.10 (3H, s), 5.00(1H, d, J=5 Hz), 5.28 and 5.58 (2H, ABq, J=15 Hz), 5.65 (1H, dd, J=5 Hz,8 Hz), 7.70 (1H, br s), 8.07 (2H, br s), 8.85 (1H, s), 9.05 (1H, d,J=1Hz), 9.43 (1H, d, J=8 Hz).

(13)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1-methyl-7-methoxycarbonyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1770, 1710, 1680, 1610 cm⁻¹.

NMR (D₂ O, δ) : 3.17 and 3.50 (2H, ABq, J=18 Hz), 3.81 (3H, s), 3.87(3H, s), 3.93 (3H, s), 5.18 (1H, d, J=5 Hz), 5.35 (2H, br s), 5.80 (1H,d, J=5 Hz), 7.43 (1H, br s), 8.00 (1H, d, J=2 Hz), 8.60 (1H, s).

(14)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1-methyl-7-carboxy-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1760, 1670, 1600 cm⁻¹.

NMR (D₂ O, δ) : 3.16 and 3.45 (2H, ABq, J=18 Hz), 4.07 (3H, s), 4.10(3H, s), 5.20 (1H, d, J=5 Hz), 5.31 (2H, br s), 5.83 (1H, d, J=5 Hz),7.37 (1H, br s), 7.91 (1H, d, J=2 Hz), 8.26 (1H, s).

(15)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[7-acetylamino-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1770, 1760, 1660, 1600 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.05 (3H, s), 3.01 and 3.33 (2H, ABq, J=18 Hz), 3.87(3H, s), 5.06 (1H, d, J=5 Hz), 5.18 and 5.22 (2H, ABq, J=15 Hz), 5.71(1H, dd, J=5 Hz, 8 Hz), 7.45 (1H, s), 8.13 (2H, br s), 8.23 (1H, s),8.30 (1H, s), 9.57 (1H, d, J=8 Hz), 10.91 (1H, br s).

(16)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[2-methyl-5-[1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1760, 1600, 1040 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.32 (3H, s), 2.92 and 3.30 (2H, ABq, J=18 Hz), 3.87(3H, s), 5.02 (1H, d, J=5 Hz), 5.26 and 5.45 (2H, ABq, J=15 Hz), 5.67(1H, dd, J=8.5 Hz, 5 Hz), 6.44 (1H, d, J=3 Hz), 8.18 (2H, s), 8.21 (1H,d, J=3 Hz), 8.35 (1H, s), 9.54 (1H, d, J=8.5 Hz).

(17)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1,2-dimethyl-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1760, 1670, 1600 cm⁻¹.

NMR (DMSO-d₆, δ) : 2.33 (3H, s), 2.83 and 3.30 (2H, ABq, J=18 Hz), 3.70(3H, s), 3.86 (3H, s), 4.96 (1H, d, J=5 Hz), 5.20 and 5.50 (2H, ABq,J=15 Hz), 5.60 (1H, dd, J=8 Hz, 5 Hz), 6.57 (1H, d, J=3 Hz), 8.10 (2H,s), 6.23 (1H, d, J=3 Hz), 8.56 (1H, s), 9.40 (1H, d, J=8 Hz).

(18)7β-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-[7-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1765, 1665, 1605, 1515 cm⁻¹.

NMR (D₂ O, δ) : 1.38 (3H, t, J=7 Hz), 2.28 (3H, s), 3.17 and 3.42 (2H,ABq, J=18 Hz), 4.33 (2H, q, J=7 Hz), 5.05-5.40 (2H, m), 5.23 (1H, d, J=5Hz), 5.85 (1H, d, J=5 Hz), 6.96 (1H, s), 7.43 (1H, br s), 7.74 (1H, brs), 7.81 (1H, br s).

(19)7β-[2-[5-Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[7-methyl-5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1770, 1670, 1610, 1520 cm⁻¹.

NMR (D₂ O, δ) : 1.33 (3H, t, J=7 Hz), 2.20 (3H, s), 3.08 and 3.46 (2H,ABq, J=18 Hz), 4.32 (2H, q, J=7 Hz), 4.98-5.47 (2H, m), 5.20 (1H, d, J=5Hz), 5.80 (1H, d, J=5 Hz), 7.35 (1H, br s), 7.63 (1H, br s), 7.70 (1H,d, J=2 Hz).

(20)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[1,7-dimethyl-5-(1H-imidazo-[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1770, 1675, 1605, 1550, 1520 cm⁻¹.

NMR (D₂ O, δ) : 2.30 (3H, s), 3.18 and 3.36 (2H, 5.16 (1H, d, J=5 Hz),5.30-5.60 (2H, m), 5.78 (1H, d, J=5 Hz), 5.80-6.20 (1H, m), 7.29 (1H, brs), 7.69 (1H, br s), 7.78 (1H, d, J=3 Hz).

(21)7β-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-[1,7-dimethyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

NMR (D₂ O, δ) : 1.30 (3H, t, J=7 Hz), 2.31 (3H, s), 3.10 and 3.40 (2H,ABq, J=18 Hz), 3.90 (3H, s), 4.25 (2H, q, J=7 Hz), 5.03-5.30 (2H, m),5.18 (1H, d, J=5 Hz), 5.76 (1H, d, J=5 Hz), 6.88 (1H, s), 7.30 (1H, brs), 7.71 (1H, br s), 7.79 (1H, d, J=3 Hz).

(22)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1-[N,N-dimethylcarbamoyl)-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

NMR (DMSO-d₆, δ) : 3.10 (6H, s), 3.28-3.70 (2H, m), 3.87 (3H, s), 5.00(1H, d, J=5 Hz), 5.15-5.68 (2H, m), 5.63 (1H, dd, J=5 Hz, 8 Hz), 5.67(1H, d, J=3 Hz), 8.01 (1H, d, J=2 Hz), 8.10 (2H, br s), 8.53 (1H, d, J=3Hz), 9.16 (1H, d, J=2 Hz), 9.45 (1H, d, J=8 Hz).

(23)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(3-hydroxypropoxyimino)acetamido]-3-[5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol) : 1770, 1660, 1595, 1510 cm⁻¹.

NMR (DMSO-d₆, δ) : 1.50-1.88 (2H, m), 2.86 and 3.26 (2H, ABq, J=18 Hz),3.25-3.55 (2H, m), 3.80-4.33 (2H, m), 4.96 (1H, d, J=5 Hz), 5.00-5.46(2H, m), 5.63 (1H, dd, J=5 Hz, 8 Hz), 6.38 (1H, d, J=3 Hz), 7.49 (1H, brs), 8.00 (2H, br s), 8.10 (1H, d, J=3 Hz), 8.36 (1H, br s), 9.38 (1H, d,J=8 Hz).

(24)7β-[2-(2-Aminothiazol-4-yl)-2-acetoxyiminoacetamido]-3-[5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

NMR (DMSO-d₆, δ) : 2.10 (3H, s), 3.06-3.38 (2H, m), 4.95-5.28 (2H, m),5.25 (1H, d, J=5 Hz), 5.40-5.60 (1H, m), 6.30-6.45 (1H, m), 6.95 (1H,s), 7.70 (1H, br s), 7.90-8.10 (1H, m), 8.30-8.36 (1H, m).

EXAMPLE 7

To a suspension of7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1-(2-formylaminoethyl)-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer) (0.74 g) in methanol (4 ml) was added concentratedhydrochloric acid (0.35 ml). The mixture was stirred at room temperaturefor 20 hours. The reaction mixture was poured into ethyl acetate (100ml). The resultant precipitate was collected by filtration, washed withisopropyl ether and dried over magnesium sulfate in vacuo to give7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1-(2-aminoethyl)-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate dihydrochloride (syn isomer) (0.76 g).

IR (Nujol) : 1780, 1710, 1670, 1640, 1600 cm⁻¹.

NMR (D₂ O, δ) : 3.30 and 3.65 (2H, ABq, J=18 Hz), 4.09 (3H, s),3.47-3.80 (2H m), 4.42-4.70 (2H m), 5.29 (1H, d, J=5 Hz), 5.36 and 5.61(2H, ABq, J=15 Hz), 5.89 (1H, d, J=5 Hz), 6.62 (1H, d, J=3 Hz), 7.57(1H, br s), 7.97 (1H, d, J=2 Hz), 8.12 (1H, d, J=3 Hz).

EXAMPLE 8

To a solution of7β-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-[5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylate(syn isomer) (13.1 g) in 1M sulfuric acid (30 ml) was added acetone (90ml) under stirring at 20° C. and the mixture was stirred for 2 hours atthe same temperature. The resultant crystals were collected byfiltration and dried to give7β-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-[5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatesulfate (syn isomer) (12 g).

IR (Nujol) : 3280, 1785, 1680, 1655, 1590, 1520 cm⁻¹.

NMR (D₂ O, δ) : 1.20 (3H, t, J=7 Hz), 2.93 and 3.35 (2H, ABq, J=18 Hz),4.05 (2H, q, J=7 Hz), 5.05 (1H, d, J=5 Hz), 5.20-5.50 (2H, m), 5.66 (1H,dd, J=5 Hz, 8 Hz), 6.45 (1H, d, J=5 Hz), 6.68 (1H, s), 7.15 (2H, br s),7.49-7.62 (1H, m), 8.18 (1H, d, J=5 Hz), 8.38-8.55 (1H, m), 9.46 (1H, d,J=8 Hz).

EXAMPLE 9

To a solution of 7β-[2-(2-aminothiazol-4-yl)-2-acetoxyiminoacetamido-3-[5-(1H-imidazo[1,2-b]-pyrazolio)]methyl-3-cephem-4-carboxylate (synisomer) in a mixture of methanol (20 ml) and water 10 ml). To thesolution was added ammonium chloride (622 mg) and the mixture wasstirred at 25° C. for 3 hours at pH 8.0. The reaction mixture wasadjusted to pH 3.0 with 1N hydrochloric acid and concentrated to 10 mlunder reduced pressure. The concentrate was subjected to columnchromatography on Diaion HP-20 using 5% isopropyl alcohol as an eluentand the fraction was lyophilized to give7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-]5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer) (2 g).

NMR (DMSO-d₆, δ) : 2.90 and 3.33 (2H, ABq, J=18 Hz), 5.03 (1H, d, J=5Hz), 5.18-5.60 (2H, m), 5.63 (1H, dd, J=5 Hz, 8 Hz), 6.45 (1H, d, J=3Hz), 6.60 (1H, s), 7.03 (1H, br s), 7.65 (1H, br s), 8.18 (1H, d, J=3Hz), 8.47 (1H, d, J=2 Hz), 9.35 (1H, d, J=8 Hz).

EXAMPLE 10

A solution of7β-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-[5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylatesulfate (syn isomer) (1.5 g) in water (80 ml) was adjusted to pH 9.5with 1N aqueous sodium hydroxide. The solution was subjected to columnchromatography on Diaion HP-20 using 20% isopropyl alcohol as an eluentand the object fractions were lyophilized to give sodium7β-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamide]-3-(5H-imidazo[1,2-b]pyrazol-5-yl)methyl-3-cephem-4-carboxylate(syn isomer) (946 mg).

NMR (DMSO-d₆, δ) : 1.20 (3H, t, J=7 Hz), 2.87 and 3.27 (2H, ABq, J=18Hz), 4.05 (2H, q, J=7 Hz), 5.05 (1H, d, J=5 Hz), 5.05-5.48 (2H m), 5.63(1H, dd, J=5 Hz, 8 Hz), 6.24 (1H, d, J=3 Hz), 6.65 (1H, s), 7.15 (2H, brs), 7.20-7.35 (1H, m), 7.93 (1H, d, J=3 Hz), 8.16-8.33 (1H, m), 9.48(1H, d, J=8 Hz).

EXAMPLE 11

The following compound was obtained by treating7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer) according to a similar manner to that of Example 10.

Sodium7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-(5H-imidazo[1,2-b]pyrazol-5-yl)-methyl-3-cephem-4-carboxylate(syn isomer)

NMR (DMSO-d₆, δ) : 1.20 (3H, d, J=7 Hz), 2.85 and 3.18 (2H, ABq, J=18Hz), 4.13 (2H, q, J=7 Hz), 5.00 (1H, d, J=5 Hz), 5.11-5.25 (2H, m), 5.63(1H, dd, J=5 Hz, 8 Hz), 6.21 (1H, d, J=3 Hz), 7.23 (1H, d, J=2 Hz), 7.91(1H, d, J=3 Hz), 8.16 (2H, br s), 8.25 (1H, d, J=2 Hz), 9.54 (1H, d, J=8Hz).

What we claim is:
 1. A compound of the formula: ##STR8## wherein R¹ isamino or a protected amino group, R² is hydrogen, lower alkyl, mono(ordi or tri)halo(lower)alkyl, lower alkenyl, lower alkynyl, phenyl,naphthyl, phenyl-(lower)alkyl, carboxy(lower)alkyl, protectedcarboxy(lower)alkyl, hydroxy-(lower)alkyl, protectedhydroxy(lower)-alkyl or a hydroxy protective group,R³ is hydrogen, loweralkyl, hydroxy(lower) alkyl, protected hydroxy(lower)alkyl,amino(lower)alkyl, protected amino-(lower)alkyl, carbamoyl(lower)alkyl,N,N-di(lower)alkylcarbamoyl(lower) alkyl or an imino protective group,R⁴ is hydrogen, lower alkyl, carboxy, protected carboxy, amino,protected amino or carbamoyl, and Z is N or CH, or a pharmaceuticallyacceptable salt thereof.
 2. A compound of claim 1,wherein R² ishydrogen, lower alkyl, lower alkenyl, hydroxy(lower)alkyl, protectedhydroxy(lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkylor a hydroxy protective group.
 3. A compound of claim 2,whereinR¹ isamino, R² is hydrogen, lower alkyl, lower alkenyl, hydroxy(lower)alkyl,carboxy(lower)alkyl, esterified carboxy(lower)alkyl or lower alkanoyl,R³ is hydrogen, lower alkyl, hydroxy(lower)-alkyl,amino(lower)alkanoylamino(lower)-alkyl, carbamoyl(lower)alkyl,N,N-di(lower)alkylcarbamoyl(lower)alkyl, or N,N-di(lower)alkylcarbamoyl,and R⁴ is hydrogen, lower alkyl, carboxy, esterified carboxy, amino,lower alkanoylamino or carbamoyl.
 4. A compound of claim 3,wherein ρR¹is amino,R² is hydrogen, lower alkyl, lower alkenyl,hydroxy(lower)alkyl, carboxy(lower)alkyl or lower alkanoyl, R³ ishydrogen, lower alkyl, hydroxy(lower)-alkyl, amino(lower)alkyl, loweralkanoylamino(lower)alkyl, carbamoyl(lower)alkyl,N,N-di(lower)alkylcarbamoyl(lower)alkyl or N,N-di(lower)alkylcarbamoyl,and R⁴ is hydrogen, lower alkyl, carboxy, lower alkoxycarbonyl, amino,lower alkanoylamino or carbamoyl.
 5. An antimicrobial pharmaceuticalcomposition which comprises as an active ingredient, an effective amountof a compound of claim 1 or a pharmaceutically acceptable salt thereofin admixture with pharmaceutically acceptable carriers.
 6. A method forthe treatment of infectious diseases which comprises administering aneffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt thereof to a human or animal.